Understudy Gene Offers Hope for Spinal Muscular Atrophy

Brooke and Brielle have spinal muscular atrophy

These beautiful sisters, Brooke (6) and Brielle (8) Kennedy, love anything Disney. And they have type II spinal muscular atrophy

I began writing about genetics decades ago, and the best thing about getting older is witnessing the development of targeted treatments for single-gene diseases that I never thought would happen. But it is happening, for cystic fibrosis, Duchenne muscular dystrophy, hemophilia, various inborn errors of metabolism, blindness, and many other conditions. The steps may be incremental for some conditions, but researchers are deploying a staggeringly diverse armamentarium of techniques and technologies to fight genetic disease, from recombinant DNA-based drugs, to enzyme replacement and substrate reduction treatments, to gene therapy, antisense compounds, microRNAs, gene silencing, RNAi, exon skipping, and small molecule approaches.

Now spinal muscular atrophy enters the arena of the possible.

SMA isn’t one of the more familiar single-gene conditions. Today is the middle of SMA Awareness Week in the UK. Some people first read about the condition in an August 13 Facebook post from Katherine Myers:

“To the little boy at the science museum, I don’t know who you are, but thank you for being amazing. You let my son play and engage with you. You helped him pick up balls from the floor when you saw that he could not. You didn’t ask what was wrong with him or why he couldn’t walk, you just saw him. Kaden is a lot like you, he is very curious and wildly smart. He wants to know how everything works. Thank you for helping him turn the lever when you noticed he was too weak to do it himself. You will probably never see this but just by being you, you make this world better.”

Sarah and Eric, Brooke and Brielle Kennedy

Sarah and Eric, Brooke and Brielle Kennedy

Brielle Kennedy was diagnosed with SMA at 16 months – before that she’d seemed fine, just a little slow in reaching certain physical milestones. Brielle’s diagnosis came soon after sister Brooke was born, just days before dad Eric went to Afghanistan with the Michigan National Guard. A month after Eric left, his wife Sarah had to phone to tell him that Brooke, too, had inherited SMA. Their activism and fundraising began instantly, and the family inspired Representative Fred Upton to sponsor the 21st Century Cures  initiative to support research on devastating childhood diseases. The Congressman and the two little girls have become close. The girls’ motto is, “I can and I will.”

In spinal muscular atrophy (SMA), motor neurons in the spinal cord degenerate. Skeletal (voluntary) muscle loses function, producing weakness and impairing mobility. Also called “floppy baby syndrome,” SMA results from mutation in the “survival motor neuron” gene (SMN1). Incidence of SMA is 1 in 10,000 in the US, and 1 in 50 people are carriers – that’s 6 million people who have one copy of the mutation.

Variants of SMA are based on clinical severity. In type I (Wernig–Hoffman syndrome), symptoms begin before 6 months, with death from respiratory failure by age 2. Type II, the most common form, is intermediate severity, with onset before 2 years. That’s what Brielle and Brooke have. Children can sit but not stand or walk alone, and may live through their twenties. In type III (Kugelberg–Welander syndrome), symptoms begin after 18 months and range from overall weakness to requiring a wheelchair. Life expectancy may be normal but weakness worsens over time. In all types, children start out life alert and happy.

As with many genetic diseases, a few individuals defy categorization. When I was a hospice volunteer I visited a 7-year-old who had type I SMA. She couldn’t move or respond and was on a feeding tube. I’d read to her but she was unable to respond in any way. Her brother, age 3, also had SMA, so perhaps other genes exerted a slight protective effect for the siblings.

SMA is a classic autosomal recessive illness: two carriers pass the disease to each child with a theoretical frequency of 1 in 4. But the genetic set-up is unusual, because the human genome includes two SMN genes. Nearly all patients have mutations, typically deletions, in both copies of the SMN1 gene, which is on the short arm of chromosome 5. The chromosomal neighborhood is a bit unstable because it is riddled with DNA sequence symmetry, including similar genes and repeats. This confounds DNA replication into making two copies instead of one, like repeating a word word in a sentence. That could be how two versions of the gene arose.

SMN2 is the second SMN gene, and people have 0, 1 or 2 copies on each chromosome 5. The most common situation is SMN1 and SMN2 splayed out in opposite orientation, encompassing half a million DNA bases. SMN2 is a little like an understudy for SMN1, because having extra SMN2 gene copies blunts the severity of SMA. Cells make a little more SMN protein.



Each gene – SMN1 and SMN2 – consists of 9 exons, which are the regions that encode the amino acids of a protein. The exons are separated by introns, the noncoding regions that are spliced out when the DNA is transcribed into messenger RNA. The two genes differ in just one DNA base, in exon 7, but it’s at a critical part of the gene called an exon splice enhancer, which controls how introns are removed. The tiny difference in SMN2 effectively silences its ability to make the protein, nearly completely but not quite.

But what if we could turn SMN2 back on in SMA patients? It’s not often that nature provides a back-up.

That’s the reasoning behind a drug candidate called ISIS-SMNRx, being developed by Isis Pharmaceuticals, a Carlsbad CA-based biotech company that has been around for many more years than the unfortunately-named terrorist group. I remember writing about Isis in the early 1990s. The company is partnering with Biogen, another big biotech that’s been around a long time.


Richard Finkel, MD, division chief of neurology and a specialist in neuromuscular disorders at Nemours Children’s Hospital in Orlando, explained the strategy of SMNRx. “The SMN1 gene is present in all animals. Only humans carry the ‘back-up’ SMN2 gene, which provides the opportunity for targeted treatment when SMN1 is deleted or mutated.”

The targeted treatment for SMA is an antisense compound. That’s a very short piece of a DNA-like molecule that forms complementary base pairs with (i.e. gloms onto) a selected part of a gene. For SMA, that’s in the crucial exon 7 that alters intron splicing.

“The beauty of this strategy is that SMN2 does make a small amount of normal SMN protein, just not very much of it due to the single nucleotide change that alters splicing. The antisense oligonucleotide (the drug) targets an alternative splice site of SMN2 to promote inclusion of exon 7, that is usually excluded, and to shift the splicing emphasis to more full length transcript,” Dr. Finkel explained.

Atticus_and_Tom_Robinson_in_courtThe relationship of SMN1 and SMN2 on the same chromosome is a little like deriving the novels “To Kill a Mockingbird” and “Go Set a Watchman” from the single huge manuscript that author Harper Lee turned in to her editors back in the 1950s. They are each in a way cut from the same cloth, two stories culled from one, with the two genes more alike than the two narratives. “Go Set a Watchman” sat in silence for more than half a century, as did SMN2 until researchers figured out how to awaken it.

FDA has given SMNRx orphan drug status and fast track authorization. When the first clinical trial protocols were filed at the end of 2011, the best that could be hoped for was to show safety and perhaps slowing of progression. But it’s much better than that. The company reported findings June 22 for the phase 2 clinical trial, and two phase 3 trials are ongoing, one for infants and one for older children.

In the phase 3 trials, 30 children who had received multiple doses of any of 4 escalating dosages in the phase 2 trial (to set baseline scores) are now receiving the highest dose every six months. The drug is given directly into the spinal cord. The phase 2 trial results analyzed so far indicate that the drug is not only safe, but seemingly effective at restoring some function.

Various “rating scales” are used to evaluate response in children with SMA (infants require different tests). Some are used for several neuromuscular conditions, such as the “Six-Minute Walk Test” to assess number of steps taken on a treadmill in that time. Children who can’t walk take the upper limb module (ULM) test, tweaked for SMA. Tailored to evaluating SMA is the Hammersmith Functional Motor Scale-Expanded (HFMSE) test. It assesses the best that a patient can do on a particular day, such as how long it takes to roll over and how long a child can hold a position, like sitting.

More than half of the children have improved in HFMSE scores, and performance on the other two measures increased too. “The natural course for children with untreated type II or type III SMA (is to) typically experience loss of muscle function that develops slowly and continually over time. A sustained increase of three or more points in HFMSE scores represents a significant departure from the natural course and is unusual for these children,” said Darryl De Vivo, MD, professor of neurology and pediatrics, Columbia University Medical Center. “Some children approaching three years of age who had been treated since infancy are showing increases in muscle function scores and are meeting development milestones that are not predicted for infants with SMA, like sitting up, rolling over, and head control,” said Amy Williford, PhD, associate director, corporate communications for Isis.

(Dept. of Energy)

(Dept. of Energy)

Most genes don’t have shadow copies to manipulate, but other approaches are targeting SMA too. At Nationwide Children’s Hospital in Columbus, Ohio, Dr. Jerry R Mendell and colleagues are testing gene therapy for children with SMA1, using adeno-associated virus serotype 9, which is delivered intravenously.

Waiting in the wings are promising preclinical (animal) studies, which always continue even as treatments reach clinical trials. PTC Therapeutics has a small molecule drug that also shifts splicing of SMN2, boosting protein production. It’s worked well in mice with a severe form of SMA, improving motor function, preserving motor neurons and the muscles they innervate, and extending life. (The mice are genetically modified and bred to have human SMN2.)

Kaden’s mom’s Facebook post has been viewed 10 million times and logged 230,000 likes. And the Kennedy family has told their story everywhere. Let’s hope that the next time SMA is in the news, it’s because of the treatment that looks so promising.

For more information, see:
Fight SMA
Cure SMA
Spinal Muscular Atrophy Foundation

The SMA Trust

Thanks to Sarah Kennedy for the photos of her family, and to NORD for telling me about them.

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Precision Medicine: Much More Than Just Genetics

Doctor and Patient with DNAWhen President Obama uttered the words “Precision Medicine” in the state-of-the-union address, I scoffed at a politician’s finally noticing a field that’s been around for decades: medical genetics. Was it another case of rebranding, as chemistry has morphed into nanotech? But the definition of Precision Medicine that has emerged is, well, precise: “An approach to disease treatment and prevention that seeks to maximize effectiveness by taking into account individual variability in genes, environment, and lifestyle.”

Last week’s publication of the Precision Medicine Initiative Cohort Program, plus an email that I received just yesterday, have convinced me that the PMI is perhaps the best research idea I’ve ever heard, dwarfing even the human genome project in its potential. A vast wealth of eclectic information will be amassed from a million volunteers who represent the nation’s diversity. They will donate blood and other tissue samples, such as nails and hair, to a biobank and actively participate at all stages.

The scope of the PMICP goes way beyond the goal of the now-defunct National Children’s Study, which wasn’t planned well enough to track environmental effects on health among 100,000 individuals from the womb to age 21, as President Clinton had proposed. And the PMI Cohort Program isn’t  just another biobank, a trend that began with Iceland’s efforts more than a decade ago. It will record practically everything about the volunteers, beyond environmental exposures and genetic information, to lifestyle, behaviors, and even their microbiomes. The report is 108 pages long, but Francis Collins, MD, PhD, director of the NIH and who called for the cohort program, describes the scope at his Director’s Blog.

DNA_sequenceWHY NOW?

A perfect convergence of technological leaps underlies the PMI:

  • Genome sequencing costs are down 10-million fold from 1998, with time collapsed from a decade to a day.
  • Improved mass spectroscopy can analyze more metabolites that can serve as biomarkers, enabling us to track more diseases and our immune systems’ responses.
  • Electronic medical records store clinical data over time.
  • Mobile health (“mHealth”) apps and technologies enable anyone to track almost anything, comparing such measurements as GPS data, pollution reports, and Blood pressure cuffrelevant physiological responses. Many of us already monitor our daily food intake, number of steps taken, blood pressure, heart rate, sleep patterns, even blood sugar levels.
  • Social media is connecting patients, creating an incredibly science-savvy constellation of online communities.
  • DNA-based ancestry testing is confirming or altering what greatgrandma told us about our geographic and ethnic origins.
  • Cell-free DNA analysis is replacing invasive biopsies.
  • Targeted therapies are replacing broader ones: Gleevec for chronic myelogenous leukemia, Kalydeco for cystic fibrosis, and the new hepatitis C drugs. Basing diagnoses on molecules rather than symptoms hikes efficacy. And the first gene therapy is expected to be approved in the US possibly during the coming year.
  • Human MicrobiomeSome patients know more about genetics and genomics than their health care providers. I wrote about one dad who presented his son’s doctor with the boy’s exome sequence.
  • The human microbiome is being dissected, revealing the genomes within and on us.
  • Bioinformatics can store, analyze, compare, and continue to interrogate floods of data.


The PMI Cohort Program may turn the practice of medicine on its head, and in so many ways, at so many levels, that my own head feels ready to explode with possibilities. Many of the ideas aren’t new, but the scale and scope are.

1. Clinical trials will be able to better select participants most likely to benefit from new therapies, based on the molecular pathology of the condition and a person’s specific genotype.

Drug Development2. Pharmocogenetics and pharmacogenomics — matching patients to drugs based on DNA information — is already done for 150 FDA-approved drugs. But such prescribing information is needed for thousands more.

3. Analysis of biomolecules other than DNA, such as lipids and carbohydrates, and associating them with specific DNA sequence variants, will provide new, more meaningful biomarkers to contribute to more accurate diagnoses.

4. Identifying loss-of-function mutations in healthy people will uncover hidden sources of disease. Each of us has a few genes that are nonfunctional or missing, but the second, normal copy of the gene compensates for having only half the normal amount of the gene’s protein product. For example, a child with Tay-Sachs disease doesn’t have the enzyme hexosaminidase A. The cells of her parents, who are healthy carriers, manufacture half the normal amount, but it’s enough to protect their brains. For a few other conditions, a half load may affect physiology or health. Carriers of certain CFTR mutations do not have full-blown cystic fibrosis, but may be prone to respiratory infections. Carriers of sickle cell disease can collapse in oxygen-poor environments or under great stress. Loss-of-function mutations are also behind several neurodevelopmental conditions. But there is so much that we don’t know about what carrying loss-of-function mutations does beneath the whole-body level. The PMI Cohort Program will ultimately identify who carries what, and analyze these data against other measures, providing insights that we can only imagine.

Bacon_cheeseburger_at_The_Habit._(14453204889)5. Not all mutations are bad, and in fact some may protect, such as mutations in the CCR5 gene that block entry of HIV into a person’s cells. Another example is the gene PCSK9. Mutations in it substantially lower levels of  LDL cholesterol, so even if a person eats triple bacon cheeseburgers drenched in BBQ sauce every day, heart disease likely won’t happen.

6. Mutations in one gene may cancel out the effects of another. A person may learn that she has two copies of the well-known mutation in the apoE4 gene that predisposes to developing Alzheimer’s disease — but doesn’t know she also has a mutation in the less-well-known amyloid-B precursor protein gene that protects against the disease. The Cohort Program will eventually deduce and decipher all gene-gene interactions, perhaps reducing the anxiety of testing one-gene-at-a-time (one good reason that FDA halted direct-to-consumer testing for single genes).

Alzheimer Disease7. Following people whose DNA indicates they should have a single-gene (Mendelian) disease but don’t, and finding similarities in the genomes of others like them, may reveal inherited protections. Spinal muscular atrophy I, for example, is a devastating disease that destroys motor neurons and is typically lethal within a year of birth. But in some families, two children have mutations in both copies of the survival motor neuron gene (SMN1) that causes SMA, but only one is sick. The lucky other also inherited a variant of a second gene, plastin 3, that counteracts the first. The interaction makes sense. Absent or abnormal SMN1 protein shortens axons, while the variant of plastin 3 protein lengthens them. The effects of the two mutations cancel each other out, and a child develops normally.

8. The rare disease community will be helped, not abandoned, by the Cohort Program. James Radke, PhD, at Rare Disease Report, pointed out that mutations in rare disease genes will be missed in the mass of a million sequenced genomes, and that it might be better to stick to mining for relevant gene variants in rare disease registries if the PMI focuses on common disorders. I thought he had a very valid concern, until this email arrived yesterday:

“Dear Dr. Lewis,

My family on my mother’s side has quite delayed aging. My grandmother, mother and myself all look a minimum of 15 – 20 years younger. My mother and I have absolutely no health concerns and have vital signs that are also indicative of people 15-20 years younger. I am 46 and my mother is 64.

I know there are world record holders that have amazingly long life spans, too, and other families which have characteristics of slower aging, like my own. Maybe there is something in our DNA, blood or proteins that is present which, through research, could be used to help patients with progeria, the rapid-aging genetic disease. Could these individuals provide information about why their bodies have a more delayed aging process than average, which in turn, could then be applied to the treatment of progeria?”

$1000My new friend is an ideal candidate for participating in the PMI-Cohort Program — and I encourage everyone to sign up. We can all help each other. Summed up last week’s report, “We believe the combination of a highly engaged population and rich biological, health, and environmental data will usher in a new and more effective era of American healthcare.”

If anyone is going to the American Society of Human Genetics annual meeting in Baltimore and/or the National Organization for Rare Disorders Summit in Washington DC (where I’ll be on the Precision Medicine panel), coming up in October, let’s meet up! (rickilewis54@gmail.com). DNA Science blog is always looking for new stories.

(Thanks NHGRI for the incredible graphics)

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Tess’s Tale: Social Media Catalyzes Rare Disease Diagnosis

Tess Bigelow (Bo Bigelow)

Tess Bigelow (Bo Bigelow)

Attention to the plight of families with rare diseases continues to grow this week, and provides a backdrop to another compelling tale of a family seeking a diagnosis for mysterious symptoms.

The National Human Genome Research Institute’s Undiagnosed Diseases Network (UDN) just announced the UDN Gateway. This online application portal will guide patients to a growing national network of clinical sites, including six new ones and two genome sequencing centers. The Gateway replaces paper-based application to specific clinical centers for the few coveted slots.

The UDN evolved from the Undiagnosed Diseases Program, announced in September 2008. It was born to step in, for selected cases, when all available diagnostic tools can’t name a condition that is extremely rare, unknown, or an “atypical presentation” of a recognized disorder. Doing so not only helps the families and others with the same syndromes, of course, but fills in the blanks of our knowledge of the human genome. The program has evaluated 800 of 3,100 applicants since 2008, diagnosing 25%. That success rate will surely soar as human genome sequences are further annotated and gene expression patterns unraveled and connected.

Although each new UDN clinical center will be taking 50 new cases a year by next summer, winning a slot is still a little like winning the lottery. But rare disease families won’t wait. And that’s where the Rare Genomics Institute comes in, a non-profit that assists families in crowdfunding the quest for a diagnosis. Their Amplify Hope Initiative started this week with ten selected families trained to crowdfund month-long campaigns. The funds will support exome sequencing to get to the bottom of each family’s diagnosis-defying medical condition.


Yankee Lou Gehrig developed amyotrophic lateral sclerosis at age 35.

Yankee Lou Gehrig developed amyotrophic lateral sclerosis at age 35.

Another route to diagnosis is through social media. I lamented last summer’s Ice Bucket Challenge for ALS because it hogged the limelight. With only 12,000 cases in the U.S. ALS (Lou Gehrig’s disease) certainly fits the 200,000-patient definition of a rare disease. But association with the eponymous Yankee catapulted the disease into public awareness, as even the most remote connection to Hollywood can do.

Besides the celebrity connection, it can be hard to figure out why the national media latches on to certain families, when so many are desperate for attention. That’s why it’s so great that rare disease families reach out to and help each other. Witness the amazing “Saving Eliza” campaign of the O’Neill family of South Carolina, who are under voluntary house arrest to keep their little girl virus-free so that she can enter a gene therapy trial for Sanfilippo syndrome type A. Any national appearance of a rare disease family can help many. Coverage of the O’Neill’s story on the Today Show led to the diagnosis of at least one other child, and their more recent appearance in People — even a photo on the table of contents page and letters the next week — may identify others.

The story of another little girl, Tess Bigelow, shows how social media can lead to a diagnosis, or at least to a research group working on a child’s specific gene, in just hours. I found Tess’s story on Facebook, and her dad Bo gave permission to reprint it here. It’s from his blog post, called “Answers” (edited for brevity). (Details about Tess’s illness are in Part 1 “This Isn’t Over,” and Part 2 “Not Giving Up“.


(Jonathan Bailey, NHGRI)

(Jonathan Bailey, NHGRI)

It is night. My wife and I are emotionally drained. The Tess webpage is live and it’s getting shared. While happy that it’s gone viral, we’re reeling from how much mental effort it’s taken to make the jump. To really try. To not give up.

So there we are, reading just before bed, knackered. Barely able to mumble to each other that we should switch off the lights and hit the hay.

Then my phone buzzes on the nightstand. I pick it up.

There’s a new email in my inbox. “To whom it may concern,” it starts off. “My name is Mike Fountain and I conduct research at Baylor College of Medicine in Houston, TX. I believe I have some answers for you and Tess.”

Why does the message say “To whom it may concern,” instead of “Dear Bo and Kate?” Because we’d set up the Tess page on portlandrootsmedia.com, and all emails were sent to the general email account for that page.

So this guy doesn’t even know our names. He only knows Tess’s name.

His message continues. “I work with this gene and these symptoms and will publish our work soon. I know of other patients.”

I know of other patients.

And he gives his contact info.

I practically drop my phone out the bedroom window, frantically typing my response. We schedule a call with him.

The next day, we’re talking to him. Mike Fountain at Baylor. We can’t get our heads around this idea. We refuse to believe it. There has to be some mistake. Like, maybe we’ll tell Mike more about Tess and her symptoms, and he’ll say, “Ah. Sorry. Not the right symptoms. Not the right gene. Sorry to have bothered you.”

But that isn’t what Mike Fountain tells us. There are seven kids that he knows of. Seven other patients. Mike’s been working with a doctor at Baylor, an MD PhD, a researcher and professor of molecular and human genetics named Christian Schaaf. And their study is all about USP7. The exact gene where Tess has a mutation. (USP7 stands for ubiquitin-specific protease 7).

Mike tells us about the other seven. They are all older than Tess. The oldest is thirteen. They’re from all over the world. Some in the US, some in Europe and Asia. Two girls, five boys. They all have developmental delay and intellectual disability. Which Tess has. Several have hypotonia, or low trunk strength, which Tess also has.

static1.squarespaceOur conversation with Mike is a welcome but scary glimpse into the future. We’re about to hear what could happen with Tess. How does that 13-year-old communicate? Can she feed herself? Does she have a social life, with friends she can recognize and ask for by name? Is she happy?

Mike asks whether Tess has seizures. In the early days, when she seemed completely checked out, we’d theorized that maybe she was having seizures all the time. A subtle kind that can incapacitate somebody and you don’t even know it’s happening. We’ve had her tested for seizures a bunch. All tests have been negative. “You might want to keep an eye on that,” Mike says. “Most of the seven have seizures.”

Is Tess autistic? Man, I wish we knew. There’s no blood test for autism. Instead, doctors look at behavior and development. And Tess is so delayed with speech and social stuff that she’s never been tested. We don’t even know if she can be tested using traditional methods. “Keep an eye on that too,” Mike tells us. “Nearly all of the seven have some form of autism”.

He asks a ton of other stuff about Tess. We tell him about her visual-processing issue and our suspicions that she has an auditory processing issue as well. We talk about her loving and cheerful nature, her voracious appetite, her tendency to bite when she’s pissed off.



In the end, it’s a match. We are so thrilled that we are laughing and crying at the same time. Mike Fountain is satisfied that Tess’s symptoms and mutation line up with his patients. He’s certain that Tess belongs in this group of seven. Now there are eight.

The most mind-blowing thing about connecting with Mike Fountain and finding this match is that it only took about 12 hours. We created Tess’s page on the morning of Wednesday, August 12th, set it loose on Facebook and Twitter, and that evening, the 12th, Mike had found it and emailed us.

But Mike didn’t discover us on Facebook or Twitter. It was on Reddit, an online bulletin board that sorts content. It uses subreddits. So if you’re into My Little Pony and smoking weed, or articles that sound like they’re from The Onion but they’re real, there are subreddits. My wife and I aren’t even on Reddit. I don’t know much about it, except that most of my friends who are into science are on there a lot.

And it turns out that there’s a subreddit for genetics: r/genetics. And it’s there that Mike discovers Tess. Someone has posted the following message: “Hi r/genetics, need your help. I have a little friend who has a mutation in the USP7 gene and we can’t figure out her diagnosis despite tons of genetic testing. We’re looking for others like her – can you point us in the right direction?”

Mike Fountain isn’t on Reddit either. But a woman he shares a lab with is. And that woman shows the post to Mike and said, “Isn’t USP7 the gene you work with?”

So who posted to Reddit? Someone with the username “Oddjobpanage,” with no photo and no identifying information. We’ve since learned that Oddjobpanage is a guy in his 30s named Harry Roman, a friend of my sister and her husband. We’ve met Harry and hung out with him a few times, but it’s been years since we’ve been in touch with him. So Harry, I can’t really express how grateful we are that you shared this. That you got it to a dude who shares a lab with Mike Fountain.

Now, why didn’t I tell you this before? If Mike Fountain got in touch within 12 hours, and if we’ve known about his study for over a month, why did we wait?

We had to. From that very first email, and in every phone call since, Mike told us to keep this under our hats. He and Dr. Schaaf have been working on a paper about the seven USP7 kids, to be published on September 11th. If word got out, if I talked about it on my podcast or blog, if we splashed it all over social media, it could jeopardize the publication and even keep Mike from reaching other families. So he made us promise not to breathe a word.

AutismThe paper came out last week, in Molecular Cell. Bo’s post interprets it, explaining the disruption in control of protein recycling that likely underlies Tess’s intellectual disability, autism, and seizures. A protein called WASH must be present within a certain concentration range for adequate control of protein recycling. Bo continues:

In all this talk about the WASH protein, the final sentence shouts out to me, almost as if the rest of the article is one of those redacted CIA documents from the Cold War, where every single line is blacked out with a Sharpie, except for one sentence, the one that’s escaped the censors. The final sentence says: “… our results suggest that chemically activating WASH in these patients may have therapeutic potential.”

There may be something we can do, some type of therapy that could help Tess.

What happens now?

Mike Fountain and Dr. Schaaf are both pretty juiced. This wasn’t a one-shot deal, where they publish and hang up their guns. This is only the beginning. The syndrome doesn’t have a name yet. For now, they’re calling it “USP7-associated genetic disorder.” Tess is going to join this group of patients. She’ll be part of the next study, and it looks like everybody wants to get started right away. Mike has already put us in touch with another family, one who was part of this study. Our families have started emailing each other, comparing notes on our kids.

And we need to find more patients. This is what social media is for. Share Tess’s page. Tell everyone you know, your hairdresser. Your mail carrier. Your accountant. The guy waiting at the bus stop with you. The kid making your sandwich at the deli. Everybody you talk to and email with and Facebook with and tweet at. You never know whether a dude named Harry, who you haven’t seen in six years, who you barely know, will turn out to be the one to make it all happen.

There are families out there. Their kid has intellectual disability and low trunk strength, with signs of autism, maybe. They’re in the dark, this family. They don’t know how to help their kid. They’ve seen a million specialists, and they have no name for what’s going on. Perhaps they’ve mapped their kid’s genome and know about USP7, but they’re ready to throw in the towel. To shrug and say, well, we’ll never know. Help them find us.”

If anyone else has a story to share, please let me know. I can’t think of a better use of this blog than to connect families with each other and with researchers.

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The Ripper Gene: A Book Review

Ripper Gene_9780765376879_HC.inddBecause I write nonfiction, I love to read fiction. But I avoid crime novels, especially about serial killers who carry out gruesome rituals on innocent young women. When a book publicist sent me info about a new book, “The Ripper Gene,” however, I couldn’t resist. The book is published by Forge, Tom Doherty Associates, which is part of Macmillan.

Written by Michael Ransom – known in biotech circles as molecular pharmacologist Michael Burczynski, PhD – The Ripper Gene is a cleverly-crafted, tightly unfolding thriller based on solid science. And that’s why it’s scary.

The Ripper Gene is a case study in genetic determinism, the idea that our DNA dictates who we are and how we behave. The protagonist, neuroscientist and FBI profiler Lucas Madden, has discovered a “damnation algorithm” genotype that predisposes those who have two copies of it to violence.

Early in the book, Madden/Ransom takes pains to explain that the damnation algorithm is more complicated than a lone serial killer gene, in jargon and then in plain English:

Michael Ransom, author of "The Ripper Gene"

Michael Ransom, author of “The Ripper Gene”

“Importantly, we don’t just look at single nucleotide polymorphisms, as scientists did in the past. We can now investigate many different aspects of human DNA – its methylation patterns, microRNA binding sites, copy number variants, insertions and deletions, just to name a few. When we examined the totality of genetic differences that can be observed, we found that key differences between violent offenders mapped to several dozen human genes … all of which are linked in one way or another to neurochemical signaling in the brain.”

But the focus indeed becomes a single gene, “ripper,” that encodes a subunit of a dopamine receptor, expressed in the amygdala. It’s a plausible set-up for the biology of violence.

XYY Revisited

We had a preview of the risks of attributing violent behavior to genetic information half a century ago. In 1961, a tall, healthy man, known for his boisterous behavior, had his chromosomes checked after fathering a child with Down syndrome. The man had an extra Y chromosome. Could that have caused his aggression?

A few other cases of aggressive men with extra Y’s were reported. Then in 1965, British geneticist Patricia Jacobs surveyed 197 inmates at a high-security prison in Scotland. Of twelve men with unusual chromosomes, seven had an extra Y. After Jacobs’s findings were repeated for mental institutions, Newsweek ran a cover story on “congenital criminals.” An extra Y became a legal defense for committing a violent crime, a connection that eventually became a plot on Law and Order and other programs.

XYYIn the early 1970s, newborn screens began in hospital nurseries in England, Canada, Denmark, and Boston, with social workers and psychologists visiting parents of XYY boys to offer “anticipatory guidance” for dealing with their toddling future criminals. By 1974, geneticists and others halted the program, recognizing that the well-meant intervention could invite a self-fulfilling prophecy.

In fact, 96 percent of the one in a thousand males with an extra Y can blame their extra chromosome for only great height, acne, and learning disabilities. But might the large size of such boys lead teachers, employers, parents, or others to expect more of them, because they appear older, especially given the learning disabilities? Might that stress of expectation provoke some individuals with an extra Y to respond with aggression?

XYY syndrome continues to be a harbinger of what may happen when we all know our genome sequences. At Bioethics Today I addressed a 2012 study by criminologists reawakening the “blame the extra Y” theme: “These simple conclusions based on fuzzy data from non-geneticists feed the genetic determinism mindset that we are our genes. And that can lead to making excuses for antisocial behavior, or losing hope of changing it, for if a trait is encoded in our DNA sequences, then we can’t control it.

That’s eerily like what Lucas Madden says when confronting the killer at the end of The Ripper Gene: “You kill because you think you have the right to kill. And it’s a conscious decision on your part. Your genetics had precious little to do with it, you piece of shit.

Amygdala_positionMAOA Revisited
A second historic example of blaming genes is the monoamine oxidase A (MAOA) gene, aka the “psycho” or “warrior” gene. The association of certain variants of this gene with violent behavior dates to a study of a Dutch family published in 1993, with 13 males who had “X-linked borderline mental retardation with prominent behavioral disturbance.”

The family members who had committed arson, attempted rape, and engaged in exhibitionism shared a mutation in a gene on the X chromosome that encodes MAOA, the enzyme that oversees metabolism of the neurotransmitters dopamine, serotonin, and norepinephrine. Like the XYY scenario, the MAOA-violence connection spread beyond the genetics community. An attorney used the “MAOA deficiency defense’ to attempt to free a client from impending execution for murder, and an appeals court in Italy reduced a convicted killer’s sentence by a year because of his MAOA status. A talk-show host joked that people with the “mean gene” should be sterilized.

Online Mendelian Inheritance in Man, my favorite source for all things human genetics, is more polite. It lists “susceptibility to antisocial behavior following childhood maltreatment” for men with certain variants of the MAOA gene.



Exploring Mutations in Fiction

The idea for The Ripper Gene grew out of a grizzly memory from the author’s adolescence, spun into a serial killer thriller with at least four possible characters who could’ve done it. As the plot unfolds, the dopamine receptor subunit gene itself becomes a powerful clue, and its recessive nature part of an eloquent metaphor. Each victim holds an apple that hides an embedded razor blade, like people fear will be handed out to children on Halloween. But it’s also an eerie symbol of the hidden nature of a recessive gene.

I don’t want to spill any spoilers. But the ultimate message of the novel is not so much the degree to which inheriting a genotype that affects a neurotransmitter receptor increases the likelihood of criminal behavior, but more about discrimination based on knowing an individual’s genotype.

Oddly, as soon as I finished reading The Ripper Gene, I picked up Summer Secrets, by Jane Green, a futile attempt to delay the coming of autumn. I was surprised to discover that it’s about a woman coming to terms with her alcoholism when she discovers that the man she thought was her father really wasn’t – and her real dad suffered from alcoholism too.

New technologies fuel the imagination. (PLOS Biology)

New technologies fuel the imagination. (PLOS Biology)

I’m glad that the idea of genetic determinism has filtered into crime novels and summer beach reads. It means that the general reading public is already thinking about what may happen once sequencing our genomes becomes routine, albeit one gene per plotline. Peter Donnelly, director of the Wellcome Trust Centre for Human Genetics, recently wrote in
PLOS Biology: “Within 15 years, there may be one billion humans whose genomes have been sequenced, in many cases with links to electronic health data.”

Will we use any of that information to excuse deviant behavior? The Ripper Gene provides a compelling look ahead.

(The description of XYY syndrome and MAOA are from my textbook, Human Genetics: Concepts and Applications, McGraw-Hill Education)

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Targeting Cancer: A Basketful of Hope

basketTargeted treatments for cancer have been extending and saving lives for more than 15 years — precision medicine isn’t a new idea in oncology. Now drugs pioneered on select, specific cancers are, one by one, finding new applications.

The first wave of targeted drug approvals were for cancers associated with specific mutations. Herceptin (traztuzumab) led the way, approved in 1998. It’s a monoclonal antibody deployed against the HER2/neu receptor that is overabundant in some aggressive and early-onset breast cancers. Robert Bazell’s excellent book Her 2 tells the tale.

In 2001 came the blockbuster Gleevec (imatinib), a small molecule tyrosine kinase inhibitor that intercepts signals to divide. Erin Zammett’s My So-Called Normal Life with Cancer relates that story. A very young editor at Glamour magazine when a routine check-up revealed chronic myelogenous leukemia, Erin’s recovery was one of the first of thousands thanks to this now famous drug.

In 2004 came the monoclonal antibody Avastin (bevacizumab), targeting vascular endothelial growth factor A to squelch the torturous blood supply feeding certain colon tumors. In 2011 Zelboraf (vemurafenib), a serine/threonine kinase inhibitor, entered the market. It blocks signals for melanoma cells to divide in people who have a specific mutation in the BRAF gene called V600. These are just a few.

(Jonathan Bailey, NHGRI)

(Jonathan Bailey, NHGRI)

The second wave of targeted cancer treatments began when the trailblazers became available for other cancers. Gleevec is now used for several blood and bone marrow cancers; Herceptin for tumors of the stomach and junction between the esophagus and stomach; and Avastin for types of lung, kidney, ovarian, and brain cancer. A study published two weeks ago in The New England Journal of Medicine reports use of Zelboraf (vemurafenib) for cancers besides melanoma, some quite rare.

The third wave of precision cancer medicines will combine targeted and other therapies. The National Cancer Institute’s Molecular Analysis for Therapy Choice (MATCH) trial will assign patients with lymphomas or solid tumors at 2,400 study sites to receive any of 20 drugs, including combinations, matched to 143 tumor mutations. Much of this matching of medicines to tumors is possible because of The Cancer Genome Atlas (TCGA), an NCI/NHGRI effort to establish mutational landscapes for the more than 200 types of cancer. In 2012, the Pan-Cancer Initiative continued TCGA to systematically explore relationships among tumor locations in the body and mutations.

The recent report on expanding use of the melanoma drug illustrates the insights that arise from these types of investigations. It is an ongoing “basket study” that bundles patients with cancers with targetable mutations that are too rare to fit ongoing clinical trial protocols. The figurative basket includes several types of traditionally-defined cancers. Edward McKenna, Senior Medical Science Director at Genentech, the manufacturer of the melanoma drug, explains. “Mutations targeted by medicines already approved or in development for specific cancers may be present in a broad range of cancers. Often these mutations are only present in a small subset of any specific tumor type. It is not practical or possible to study every medicine and target in every tumor type. Grouping diverse tumors into basket studies allows us to efficiently study them and pursue further evaluation of any promising activity.”

The NEJM study looked at BRAF V600 mutations in colorectal cancer, non–small-cell lung cancer (NSCLC), and the much rarer Erdheim–Chester disease, Langerhans’-cell histiocytosis, cholangiocarcinoma, anaplastic thyroid cancer, and multiple myeloma, as well as a few “orphan” cancers. From 2012 to 2014 the 122 patients from 23 centers worldwide took the pill twice daily.

Q and A

José Baselga, MD, PhD, (Memorial Sloan Kettering Cancer Center)

José Baselga, MD, PhD, (Memorial Sloan Kettering Cancer Center)

José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center and lead author on the recent NEJM paper, was kind enough to speak with me about the exciting study results.

RL: NBC Nightly News on August 19, when the study was published, showcased a 59-year-old jazz pianist diagnosed with glioblastoma two years previously, whose tumors had vanished following treatment with vemurafenib. Can you describe another notable recovery among the participants?

JB: Yes, The other situation in which treatment with the drug will probably be implemented very soon is Erdheim-Chester disease (a rare form of non-Langerhans cell histiocytosis, it is an adult-onset cancer of tissue macrophages that causes organ failure and bone pain). 50% of patients have the BRAF mutation. This disease has no therapy whatsoever. The first patient we treated had a huge response. She had been on the way to hospice. She couldn’t walk. Two weeks after joining the clinical trial she came back, walking and feeling fine. It’s been over a year since treatment and she is absolutely asymptomatic. We had patients from all over the place coming to be treated on this protocol and every one had tumor shrinkage. None progressed. It was remarkable.

Another great example is non-small cell lung cancer, not only because of the high response rate but because in lung cancer it is common practice to test for EGFR and KRAS mutations, so BRAF should be part of the panel. (Eight of 19 patients with NSCLC had partial responses, median progression-free survival was 7.3 months and is ongoing, and preliminary 12-month overall survival was 66%.)

RL: It must be difficult to recruit volunteers who haven’t been treated, yet that is the optimal way to evaluate a candidate drug. In the study, 89% of the patients had already been treated for their cancers. Will future targeted treatments be given earlier in the clinical trial process?

JB: Patients typically presented at stage 4 and they’d received whatever therapy is approved for their type of cancer, and at that time patients were checked for mutations. I think that as we move on, we will be doing genomic testing up front at the time of diagnosis, and these treatments can become frontline.

RL: David J. Hunter from the Harvard T. H. Chan School of Public Health and Ralph D’Agostino, Sr, from Boston University write in an accompanying Perspective that “the response to a specific mutation is likely to depend on the anatomical site of origin” and that predictions based on mutations “are overstated.” What is the relationship between diagnosis based on location (“conventional tumor nosology”) and diagnosis based on mutation (“molecular nosology”)? Are they both important?

Cancer is a choreography of mutational steps. (Darryl Leja, NHGRI)

Cancer is a choreography of mutational steps. (Darryl Leja, NHGRI)

JB: The pendulum has swung. When we began to do studies with gene mutations, testing for the genes we knew and thought were the drivers, there was a school of thought that perhaps the genes and not the tissue of origin would dictate the behavior of the tumor and what therapy would need to be offered to these patients. So people were saying instead of having a breast clinic we’d have a BRAF clinic and a KRAS clinic and a HER2 clinic and so forth. What we’ve learned is that the driver mutation matters, but the tissue of origin is also important. You cannot ignore one or the other; you have to take them together.

RL: Were any of the study results surprising?

JB: Yes, for colon cancer. BRAF colon cancer has a very poor prognosis and median survival of 3 months. We began to treat patients with a single agent (vemurafenib) and had 0% response, not a single patient responded. We were about to close the study and call it a day when two papers were published, one in Nature and one in Cancer Discovery, that said that blocking BRAF activates the EGF receptor. The way to treat these colorectal cancers, then, is to use both a BRAF inhibitor and an EGFR inhibitor. We modified the protocol, adding the EGF receptor antibody cetuximab, and BAM! We saw a tremendous number of responses. We learned that in colon cancer when you block BRAF you also have to block the EGF receptor. This doesn’t happen in lung cancer and in Erdheim–Chester disease.

So before targeted prescribing gets easy it’s going to get complicated, because the tissue-of-origin matters and we will have to deal with both that and the mutation. So our dream of the BRAF clinic goes out the window, and whatever replaces that dream will be complex. These results point to the importance of cell lineage.

RL: TV ads abound for personalized cancer treatment centers, with soothing words and warm fuzzy images. Are such genome-based initial treatments for cancer as available and accessible as these pitches project?

JB: Precision medicine is a buzzword and it has lost some of its value by overuse. Today we have a precision medicine capacity to sequence the genomes of tumors and identify some mutations and based on that information, we might be able to propose tailored treatment. In my opinion that only happens in academic institutions that have research background with serious sequencing efforts.

I think we should stick to the facts. When people announce precision medicine on TV, that’s wrong. I’d never do it. We need to take it seriously and be humble and take a step-by-step approach. At Memorial we are conducting 25 to 30 basket trials, and we offer them to the patients. But this is a work-in-progress. We have a duty to not oversell this to the public.

Testing tumor DNA in the bloodstream is replacing biopsies for some cancers. (Jonathan Bailey, NHGRI)

Testing tumor DNA in the bloodstream is replacing biopsies for some cancers. (Jonathan Bailey, NHGRI)

RL: Where do you see cancer treatment options 10 years from now?

JB: We are going to be able to look at mutations in the blood in a way that will be easy, fast, cheap, and reproducible. We will not only know the mutations, but also how the tumor is evolving to those mutations and the mechanisms for resistance to therapy. We cannot biopsy a tumor every 2 weeks or even months, but we can check the blood as much as we like. That will enable us to use a perfect combination of therapies.

But I don’t think we will cure many patients with just with one therapy. Every tumor has a repertoire of pathways and responses to survive. That repertoire is finite. It has an end. There won’t be a single therapy, so we must be able to combine therapies and identify responses. Then, when things get messy, with multiple mutations far beyond any we could treat, we’ll have the power of immunotherapy. Signatures of genomic alterations predict benefits to some immunotherapies. That is, if a tumor acquires more mutations, there’s a higher likelihood that immunotherapies will identify a tumor as foreign.

Drug development is a risky business. More than half of candidate drugs that look promising in the research lab will ultimately fail. More than a quarter of drugs that reach the clinical trial stage will be rejected as ineffective. However, the wealth of genomic information now available through public databases - in particular, the rapidly growing number of known associations between diseases and specific genes - may significantly improve the drug-development success rate.  At least, success rates will improve if drug developers let genomics guide their choice of molecular targets for research, according to a team of pharmaceutical industry and academic scientists.

(Ernesto del Aguila, NHGRI)

Within 10 years, we’ll have the capacity to check more frequently in a readily available fashion. And that is going to enable us to use appropriate combination therapies and also combine immunotherapies and targeted therapies. That’s where we’re going. I’m very hopeful!





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Another Evil TV Geneticist on Netflix’s “Between”

1000px-Mad_scientist.svgTen years ago this month, I attended the Catalyst Workshop at the American Film Institute. The week-long program taught screenwriting to a dozen scientists, with the hope that we’d somehow help Hollywood get the science right.

But what we learned during that fabulous week, dissecting films such as The Day After Tomorrow,”  meeting top studio people and even pitching ideas, is that the science just doesn’t matter. Although I agree that story and characters are paramount, getting the science right doesn’t take much effort, and can not only improve plausibility, but also accurately portray scientists. Geneticists in particular seem especially vulnerable to villianizing.

My latest target for tarnishing the image of geneticists is Between,” a six-episode Netflix offering from Canada. (Yes, I know Halle Berry’s hybrid son on Extant has something to do with a virus, but I gave up two episodes ago.)

Between” is an amalgam of familiar themes. It’s Logan’s Run, Under The Dome, and Lord of the Flies, with a small town setting like that of Wayward Pines, which I blogged about recently. And like those shows, the focus is on the characters and their relationships, with the predicament a backdrop that fuels the interactions.

So now we have Between. In the town of Pretty Lake, over the course of a few days, everyone aged 22 and older suddenly gasps, bleeds from the nose, and dies. The government quarantines the town and the young folk pile up the bodies of their elders and have a huge bonfire. Early in episode one, a main character, a geeky young man named, of course, Adam, mentions his father, a mysteriously missing geneticist. This is repeated throughout the early episodes. Foreshadow the mad scientist.

A nice touch is the accurate depiction of a major character who has Down syndrome. But one scene dangerously got insulin shock ass backwards. A boy with type 1 diabetes collapses from days without insulin and everyone yells “He’s in insulin shock! Give him candy!” Without insulin, how would his cells take up the glucose? Who vetted that script?

Soon, the people in Pretty Lake and the talking heads on their screens deem the culprit a virus. My husband Larry (a chemist) and I hung on through all six episodes to learn exactly how a virus could tell that a person has reached age 22.

We learn in the final episode, when the crazy nameless geneticist shows up via a tunnel that perhaps comes from Wayward Pines, that he engineered the virus. He cleverly included a bit of his own DNA so that he and his son would be immune. Note to the show’s writers: a parent and a child are not genetically identical. Nor do they have the same exposures guiding development of their immune systems.

The evil geneticist was working alone on the virus, because the government sends in unwitting workers wielding needles to “vaccinate” the town’s young survivors, supposedly so the quarantine can be lifted. But no. The shots will kill the young people to protect the rest of the world, as the clueless shotgivers over age 21 become victims, bleeding and dropping.

Larry and I were sorely disappointed with the ending, which did nothing to satisfy the craving of the scientifically-minded to understand how things work.

The geneticist explains how the virus kills people over 21 with a lot of posturing, emitting a barrage of inappropriate technical terms, concluding inexplicably with something about the ozone layer. It all speeds by too fast to process, but the spouting renegade geneticist seems to have invented the virus to fight overpopulation. I think. The focus is much more on teen angst involving a pregnancy and jealousy than how a virus can tell how old someone is.

When Adam parrots his dad’s message to the others, that the killer virus homes in on “the biological clock,” everyone nods with comprehension. But that term refers to circadian and other biorhythms, not a FitBit like contraption embedded in our spleens that flashes our exact ages. Basic Bio 101 writers! But it’s easy to see how that sort of error might have come up: oversimplification in a news release, which means oversimplification in the articles that spawn from it. The news release headline “Leicester scientists to unlock the secrets of the biological clock” actually refers to telomeres, the tips of chromosomes that whittle down with increasing age. Aha!



The only reason that I watched “Between” to begin with was in anticipation of using telomeres in an apocalypse story. Shrinking chromosome tips are like cellular tree rings in reverse, disappearing rather than accruing with the passage of time. With repeats of TTAGGG lopped off one by one from chromosome ends as time goes on, marking the number of cell divisions, telomeres are more quantitative than gray hairs, achy joints, and wrinkles.

In telomeres, Nature provided the perfect plot point, if only the show’s writers had looked.

The telomere clock dates back to the famous “Hayflick Limit” of 40 to 60 mitoses for cells in culture. In the 1950s, Leonard Hayflick, PhD, was a young researcher at the Wistar Institute in Philadelphia. He wanted to see what the fluid around cancer cells would do to normal cells from human embryos and fetuses. At that time all cells were thought to be immortal, dividing unceasingly. “Today if I did that using federal research dollars to grow tissue from human embryos or fetuses, I would go to jail,” he told me a few years ago for my essay collection.

800px-Wooden_hourglass_3Hayflick had wanted to run replicates of his experiment simultaneously, but the supply of material was erratic. “In my incubator at any given time, I’d have 12 to 20 cultures going, each marked with a different start date.

He soon discovered something strange. “Despite the fact that I used the same technician, the same glassware, and the same media, the cells in culture the longest stopped dividing, while the young cultures luxuriated. That shouldn’t happen. It intrigued me, so I began to look at what was going on.”

Hayflick’s fetal cells died after being moved a certain number of times, each move triggering cell division. He and colleague Paul Moorhead repeated their astonishing experiments over and over, with the same results – cells obeyed some sort of internal clock that marks the number of cell divisions. Freeze cells at division 20, and when thawed, they’d pick up where they left off, dividing 20 to 40 more times.

But it’s hard to change dogma and get published. And so Hayflick and Moorhead “sent the luxuriating cultures – the young ones – to the grey eminences of the field. We would tell them, ‘by May 20th to 30th, the cells are going to die.’ When the phone started ringing between May 20th and 30th, we decided to publish. If our work went up in flames, we’d be in the company of the grey eminences,” Hayflick told me. After a stinging rejection from one journal, the findings were published in Experimental Cell Research in 1961.

Discovery of the Hayflick limit founded what we now call telomere biology. Many others, including Elizabeth Blackburn, Carol Greider, and Jack Szostack, who shared the Nobel Prize for Physiology or Medicine in 2009, discovered the DNA sequence of human telomeres and how they function as fuses, marking biological time. DNA polymerase cannot replicate DNA at the end of a strand, unless an enzyme called telomerase tacks on more repeats – as happens in cancer cells. So Pretty Lake might have had a few cancer patients hanging around with the quarreling teens and kids. Their chromosome tips would appear young.


(Claus Azzalin, ISREC)

(Claus Azzalin, ISREC)

Larry and I eagerly awaited a character turning 22 to find out how the virus tracks time. Indeed, a pretty and popular teacher celebrates her 22nd birthday midway through episode 4, and sure enough, within minutes, spews nasal blood and expires. How could that have happened? After all, telomere shrinkage is not a discrete and uniform phenomenon. All 21-year-olds don’t have x number of TTAGGGs and a 22-year-old x-1.

I’m imagining deploying a virus that targets the telomeres using a form of genome editing (CRISPR/cas-9, TALENs, or zinc finger nucleases) and only integrating into a host chromosome if the number of repeats is below a certain threshhold. Then, the virus induces hemorrhage, perhaps by turning off transcription of various clotting factors. (Readers please elaborate or pose alternate hypotheses.)

Reviewers trashed Between for a lot of reasons – too derivative, “ho-hum,” a “familiar ensemble soap opera with conspiracy-theory embroidery,” and Hollywood Reporter’s “It’s the end of the world as they know it, and viewers won’t care.” None that I could find mentioned the spotty science.

Scientists don't create monsters.

Scientists don’t create monsters.

I’m disturbed about the missed opportunity to imagine how a virus could take out an entire huge age cohort of humanity. But I’m much more disturbed about the tired stereotype of the mad scientist, especially the ego-driven geneticist who tailors a mysterious and dangerous virus to control human population growth. It’s not only absurd, but in this age of Ebola epidemics, and fear of vaccines and genetic modification, the ideas behind Between and the events at Pretty Lake are downright dangerous.

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Disappearing Down Syndrome, Genetic Counseling, and Textbook Coverage

Doctor and Patient with DNALast week, several people sent me a perspective piece by bioethicist Art Caplan in PLOS Biology, “Chloe’s Law: A Powerful Legislative Movement Challenging a Core Ethical Norm of Genetic Testing.” The concise and compelling article considers legislation to mandate that genetic counselors talk to their patients more about positive aspects of having a child with trisomy 21 Down syndrome.

Studies show that as availability of prenatal screening (for risk) and testing (for diagnosis) for the condition have increased, births of affected children have decreased. That is, most pregnant women who learn that the fetus has trisomy 21 Down syndrome end the pregnancy. Yet genetic counseling is, historically, largely value-neutral or “non-directive.” Offer the medical facts, explain how tests work and what results mean, listen, and try to intuit the patient’s views to guide word choices. (“Termination” vs “abortion,” for example). Answer questions, but don’t try to sway clinical decision-making.

At least two hypotheses can explain the declining numbers of newborns with trisomy 21.

#1: Genetic counseling is influencing decisions to end affected pregnancies. That’s the assumption behind the legislation that Dr. Caplan discusses.

#2: Parents-to-be and the general public do have access to a great deal of information about Down syndrome and many of them make informed choices. They are electing not to bring children into the world who would face a high likelihood of having certain medical and cognitive problems.

I concur with Dr. Caplan that mandating genetic counselors to more positively spin life with trisomy 21 Down syndrome may obscure the medical and scientific facts, misleading patients.

booksPLOS BLOGS suggested that I weigh in on the matter, and I can, from two perspectives that complement Dr. Caplan’s. I’ve been providing genetic counseling since 1984 for a private ob/gyn practice, and I’ve written eleven editions of a human genetics textbook for non-science majors, starting in 1993.

Throughout the 1980s and 1990s, I often met with women who were of “advanced maternal age” (35+) explaining the benefits and risks of having the invasive procedures amniocentesis or chorionic villus sampling (CVS) to check fetal chromosomes. But since the Internet arrived, I do very little counseling of this type because patients can learn much of what I’d tell them on their own. Today patients can know more about genetics than their physicians.

The editions of my textbook chronicle the possible link between the increase in prenatal testing and the shrinking population of people with trisomy 21. Each new edition arises from updating and a wealth of feedback: from instructors and students, from researchers I interview, essays contributed by families, and most importantly, what I’ve learned at professional meetings, where talks can be months ahead of publications.

Like genetic counseling, textbook coverage of trisomy 21 already presents the negatives and positives.

21_trisomy_-_Down_syndromeMost of my book’s information about trisomy 21 is under the heading “Abnormal Chromosome Number.” I can’t be politically correct about that – normal means “common type” and an extra chromosome is not common. The section expanded abruptly at edition 4 (2001) as chromosome maps filled in with findings from the first sequenced human genomes. But the introduction remains historically accurate, even if the language is offensive today:

“The characteristic slanted eyes and flat face of the Down syndrome patient prompted Sir John Langdon Hayden Down to coin the inaccurate term ‘mongolism’ when he described the syndrome in the 1880s. As the medical superintendent of a facility for the profoundly mentally retarded, Down noted that about 10% of his patients resembled people of the Mongolian race. The resemblance is coincidental. Characteristic facial features are associated with many inherited disorders. Males and females of all races can have Down syndrome.”

Early editions then described the signs and symptoms, followed with: “These people tend to have warm, loving personalities and enjoy art and music. Intelligence varies greatly, from profound mental retardation, to those who can follow simple directions, read, and use a computer. One young man with Down syndrome graduated from junior college; another starred in a television series.”

DrillIn the mid editions I added comments from parents that addressed the subtleties of the condition. “He once dialed 911 when he stubbed his toe, because he’d been told to do just that when he was hurt,” one mother told me. I chose photos that showed young people with Down syndrome doing things – cooking, painting, reading, a little girl banging a toy xylophone. But then I had to respond to reviewers’ criticism that students couldn’t distinguish the “stories” from “what they had to know for the test.” Gradually, the human details that I so love to write about became boxed readings, captions, and tables.

Responding again to reviewer feedback, I shortened coverage of what parents can do to help their child, instead focusing on the science. Edition one mentioned the value of hanging a colored mobile over a child’s crib. That went. Edition eleven explains how researchers have harnessed X inactivation to shut off the extra chromosome 21 in cells of people with Down syndrome, providing a new way to study the pathogenesis. But I never sacrificed the humanity. Opposite a figure on the new technique a photo shows a young woman intently painting a portrait of a tree. The caption: “Many years ago, people with Down syndrome were institutionalized. Today, thanks to tremendous strides in both medical care and special education, people with the condition can hold jobs and attend college. This young lady enjoys painting.

I often give patients pages from my textbook, because it offers both sides. The coverage has always included the hard facts that genetic counselors impart: “About half of babies with Down syndrome die before one year of age, often due to malformations of the heart or kidneys. Other patients must undergo heart surgery or suffer often from common illnesses.” Complications also include poor immunity, intestinal blockages, increased leukemia risk, and the high risk of developing Alzheimer disease in later years. But then the balance: “However, some people with Down syndrome are relatively happy, healthy children and young adults. Unfortunately, the test that diagnoses Down syndrome in a fetus cannot detect how severely affected the child will be. The decision of whether to terminate such a pregnancy or raise a child with Down syndrome is very difficult.” 

ageThe book is more about the science than counseling, explaining chromosome imbalances and the puzzling maternal age effect. We’ve come far from the 1909 study that blamed “maternal reproductive exhaustion.” And the list of genes implicated in the syndrome has grown as the human genome has given up more of its secrets. Before that, we could only deduce the responsible genes from individuals who had partial third copies of  chromosome 21.

Bioethics explosively entered the Down syndrome coverage in edition 9 (2010). A boxed reading analyzed a study from Denmark cited in Dr. Caplan’s article. Government researchers there tracked trisomy 21 cases after broadening availability of screening and diagnostic testing. From 2000 to 2006, the number of affected newborns was halved, those diagnosed prenatally increased by nearly a third, and the number of diagnostic tests (CVS and amniocentesis, which are more invasive than maternal blood test screening) fell by half.

The trisomy 21 story really changed in the current edition, with the boxed reading “Will trisomy 21 Down syndrome disappear?” It considers the impact of screening cell-free DNA in the maternal circulation for fetal DNA. Available since 2011, it’s leading to diagnoses in women under 35, while enabling many pregnant women over 35 to avoid invasive tests. The box quotes two New Zealand researchers who published a paper in May 2013 that enraged several groups into demanding the bioethicists’ resignations. To quote from the paper would be out of context. But they say what I suspect at least some genetic counseling patients are thinking when weighing their options and choosing to end pregnancies to avoid the possible medical risks and realities of Down syndrome.

Brian1In the 12th edition of my book, I’ll discuss legislation, like Pennsylvania’s Chloe’s Law, that Dr. Caplan so artfully describes. I agree with him that if laws compel genetic counselors to talk more about the happy healthy xylophone-banging little children, and less about the toddlers who sport scars from heart surgeries or develop leukemia, patients might leave counseling sessions with skewed views of life with an extra chromosome 21.

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Gene Splicing in Lice and the Challenge of Clothing

174px-Body_liceA terrific article recently published in Molecular Biology and Evolution, “Alternative Splice in Alternative Lice,” provides a compelling example of maximizing genome information – adaptation of the louse Pediculus humanus to the new habitat created when our ancestors invented clothing.

Many parents encounter head lice when their children are sent home from school with instructions to get rid of the horrible rice-krispie-like eggs (“nits”) clinging to their scalp hairs. A good washing won’t do it. Medication and clunky combs do very little alone. The sooner the poor parent realizes that meticulous nit-picking is the only solution, the sooner the nightmare ends.

But consider the louse’s point of view.

Nitpicking isn't easy

Nitpicking isn’t easy

Lice live on us so that they can drink our blood, with a little help from bacteria that provide the B vitamins needed to extract maximal nutrients from their meals. Head lice lay their eggs on our hair shafts, gluing them in place. These are the much more common variety. They don’t carry disease, and are more of a colossal annoyance than anything else.

Body lice deposit their eggs in clothing seams, mostly in the armpits and waistline. The nymphs that hatch, looking like tiny adult lice, must move to the skin for their blood meals.

An infestation of body lice may cause an itchy rash if the host has an allergic reaction to the bites, but the tiny beasts can also spread disease — typhus, trench fever, and relapsing fever. Body lice aren’t nearly as easy to acquire as the head lice that easily jump scalps when kids share hats. They’re seen where people can’t bathe or change clothing often enough – homelessness, combat, natural disasters. (Pubic lice, Pthirus pubis, are a different animal entirely and came from gorillas.)

(J. H. Matternes)

(J. H. Matternes)

Since we split from our shared ancestors with chimpanzees about six million years ago, until the invention of clothing about 170,000 years ago, lice enjoyed the vast landscapes of hairy hominins. So how did the insects cope with their shrinking turf?

The two types of lice haven’t (yet) separated into two species to suit their different habitats. They will mate under laboratory conditions, although not in the wild. The lice look alike, at least to us – the body ones are slightly larger.

The louse genome is small and the insect shares 90 percent of its genes with other insect species. Rounding up the usual suspects of evolutionarily-conserved genes, such as those that encode the cytochromes and ribosomal RNAs, found few distinctions between the two types of lice. But considering a genetic mechanism called alternative splicing revealed how lice access their genomes in different ways when confronted with starkly different habitats.

Gene splicing

Gene splicing

Back in 1978, when I was in grad school learning that genes are continuous stretches of protein-encoding DNA, the idea of and evidence for “genes in pieces” arose. This discovery was a game-changer in the history of genetics. At first thought an anomaly, we’ve since learned that in fact most genes come in pieces. Stretches called introns, which do not encode protein, lie between the protein-coding segments, called exons.

Genes mix and match exons by the removal of introns, a little like selecting outfits from a vast wardrobe. This mosaic make-up of genes facilitates rapid genetic change without permanently altering the genome.

Alternative splicing generates new versions of genes in two ways: introns can stay in when they should be jettisoned, or exons skipped. The discovery that exon skipping can counteract a disease-causing mutation has been harnessed to treat disease.

When our ancestors began to cover their nakedness, lice that had previously enjoyed the expanse of the human anatomy found themselves like forest dwellers plunked into a desert. Alternative splicing might have enabled the insects to adapt, according to the new study.

A nit clings to a hair shaft.

A nit clings to a hair shaft.

Araxi Urrutia from the University of Bath and colleagues from the Universities of Illinois, Notre Dame, and Massachusetts found alternative splicing in about a third of the louse’s genes – 3,598 in either head or body lice, 1,415 just in head lice, and 2,183 just in body lice.

The researchers looked first at categories of genes that might be expected to differ between head and body lice – those affecting immunity or reproduction. Immune system genes didn’t differ in expression, but reproductive genes are indeed spliced differently. It makes sense that successfully laying eggs in the seams of fabric is a different skill than doing so along hair shafts.

Next the investigators took a more unbiased approach by identifying broad classes of genes based on function that are spliced differently in head and body lice. This time, they found major differences in development and in the nervous system.

256px-Human_head_louse_eggDistinctions are eclectic. Differences in the lining of the developing ovary affect the relationship of the insect with its endosymbiont, the vitamin-providing bacteria that must survive the more sporadic blood meals that come with the shrinking habitat fabric foists on the insects. Differences in the development of the salivary glands enable body lice to spread the three infectious diseases to their hosts. And the same gene variants of the nervous system that establish the castes of social insects may foster the sensory and behavioral strategies necessary for body lice to survive on the “human clothing environment.”

In social ants, bees, and termites, environmental factors regulate alternative splicing through methylation of regulatory regions of certain genes. Early in development these changes set into motion the nuanced phenotypes that sculpt castes. Might similar alternative splicing have enabled head lice to expand their range?

183px-Pediculus_humanus_on_a_lice_combGiven time and our continued tendency to wear clothes, will the head louse and body louse one day no longer be able to mate?

This paper illustrates why I love science. The work is beautiful in its logic. The researchers even posed an alternate hypothesis: that the stress of  living on clothing causes a general upheaval of the alternative splicing process. But that wouldn’t explain the consistent findings.

The very best science explains what we observe yet raises further questions – that’s why the phrase “scientific proof” makes me cringe. The investigation of “alternative splice in alternative lice” also provides yet another glorious illustration of the adaptation that could lead to evolutionary change.

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Midsummer Updates at DNA Science

Sonn and grandson (4)Summer is half over, so I thought I’d update a few posts.

A year ago, I frantically wrote about my young friend in Liberia, Emmanuel Gokpolu, and his pleas to help stop Ebola. Emmanuel and his loved ones survived the epidemic. When Eman’s medical education stopped when schools shut and several instructors died, he and his friends took to the streets to spread the word about how to avoid infection. The people of Liberia were saving themselves before the US began to take things seriously, only when the first case happened here.

Medical school in Monrovia has started up again for Eman, but only part time due to loss of people and resources. So he’s looking to continue his education, perhaps in Ghana, South Africa, or Nigeria. Even though Ebola has ebbed to a few cases, infectious disease is a way of life in Liberia. Eman spent his birthday last week recovering from malaria and typhoid fever. He says hi!

Great news! An article in The Lancet just announced a very promising Ebola vaccine!

On January 1, DNA Science covered an inherited disorder called adult polyglucosan body disease. It’s often misdiagnosed, because the symptoms are common. Dragging feet = ALS. Numb extremities = peripheral neuropathy. Numbness + fatigue = MS.

Researchers at Rabin Medical Center in Israel report in the current Journal of Neurology on 30 individuals with APBD, all initially misdiagnosed. Nearly a third had undergone futile, incorrect treatment. More than half of the men were told their urinary frequency was due to an enlarged prostate – some even had the organ removed!

The investigators blame the errors on “physicians’ unfamiliarity with the typical clinical and imaging features of APBD.” To remedy that, the Adult Polyglucosan Body Disease Research Foundation has developed a checklist of symptoms to help neurologists identify the zebras among the horses. And Ruth Kornreich, MD, associate professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mt. Sinai and colleagues recently determined that the carrier rate for APBD in the Ashkenazi Jewish population is a whopping 1 in 68, and have added it to their genetic screening panel.



Back at the beginning of the year, I wrote that “The APBD story offers a powerful example of the evolution of classifying disease by phenotype to the precision of classifying by genotype.” Perhaps because of President Obama mention of “precision medicine” in his state of the union address a few weeks later, an Israeli company has offered to support development of treatments for APBD. I don’t know any details, but the much-needed funding depends upon establishing a patient registry of 200 individuals, and APBDRF.org needs more people to sign up.

So … if you have numbness, cramps, stiffness, or a heavy feeling in your hands, feet, arms, and/or legs; muscles that are twitchy or sore; fatigue; foot drag; stumbling; and urinary frequency, please check out the foundation and talk to your health care provider about the possibility that you may have this condition. Sign up for the registry at APBDRF.org!

Wayward_Pines,_a.k.a_Agassiz,_BCLast week’s post concerned the ending of the Fox TV series Wayward Pines, in which the remnants of humanity are catapulted (via freezing) 2,000 years in the future, to battle the aberrant creatures that our species will become.

The ending didn’t disappoint. The “first generation,” the high school crowd being groomed to be the future, had more or less stayed in the background, but then they amassed and emerged to get rid of the elders. Rather than the peaceful, willing drifting off to Carousel of over-30s depicted in the dystopia of Logan’s Run, the older folk of Wayward Pines were murdered. The very last scene shows a few mangled characters displayed on light poles for all to see, like the final scene of the film Spartacus with bodies splayed on crosses.

I found the ending of offing the elders disturbingly relatable. Try looking for a job if you’re over 55. Check out the photos on LinkedIn. For a variation on this theme and a great summer read, try The Knockoff. A 40-something executive editor at a Vogue-like magazine returns to work after time off for cancer treatment to discover that her 25-year-old former assistant has gone off to Harvard Business School and is back, in charge, and has turned the magazine into an app.

Knowing what I do about the textbook industry (I just did a podcast on this, On the Difference Between Writing About Science and Science Writing/), the death of magazines and books made from dead trees is more likely than Homo sapiens evolving into the ghouls of Wayward Pines in just 2,000 years.

Eliza and Beckham O'Neill, the cutest kids ever.

Eliza and Beckham O’Neill

I often write about families whose kids have had gene therapy or that have made gene therapy possible for others. Here are a few updates.

Eliza and Beckham O’Neill are still staying at home to avoid contracting any nasty viruses that could keep Eliza out of a gene therapy trial for her  Sanfilippo syndrome type A.

Yesterday I received an invitation to the 17th Annual Canavan Charity Ball, sponsored by Canavan Research Illinois, which means that Max Randell will be turning 18. I can hardly believe it!

Max had gene therapy at 11 months of age for Canavan disease and again a few years later, and will have survived about a decade longer than expected. Sadly, this year’s ball is in memory of Isaac Michael Levin, who died of the disease at just 18 months of age.

Max Randell

Max Randell

“Max and Isaac shared an immediate bond and were able to communicate with each other. It was beautiful and amazing to watch,” wrote Ilyce, Max’s mom, in the invitation. And it’s true. Although Max can only blink, he can communicate – I’ve seen it.

Corey Haas

Corey Haas

Corey Haas, about to turn 15, is doing what kids around my neck of the woods do midsummer – swimming, fishing, hiking. He’s doing great. Without the gene therapy that he had a few years ago, he’d be nearly completely blind, from Leber congenital amaurosis, RPE65 type. The phase 3 clinical trial for that gene therapy is well underway at the University of Pennsylvania and at various stages in several other projects.

Hannah Sames awaits her turn for the gene therapy for giant axonal neuropathy that got underway at the University of North Carolina a few months ago. Although her family is largely responsible for the clinical trial, Hannah’s immune system must be suppressed before she can participate. But the trial for GAN is paving the way for a trial for infantile Batten disease. Dr. Steven Gray is heading up both projects at UNC.

Taylor King

Taylor King

DNA Science has profiled Taylor King, a beautiful young woman who was diagnosed with Batten disease in 2006, at age 7. Her family’s organization Taylor’s Tale has been instrumental in funding gene therapy research at UNC. And thanks to the efforts of Taylor’s mom Sharon and many others, on July 28, the North Carolina General Assembly unanimously voted to establish the state’s Advisory Council on Rare Diseases. Now other states are calling to ask how they did it.

Taylor turns 17 on August 19. Happy birthday Taylor!

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Is Wayward Pines Genetically Plausible?

Wayward_Pines,_a.k.a_Agassiz,_BCTonight is the final episode, ever, of Wayward Pines, the 10-episode FOX television show that’s the best sci-fi I’ve seen since the X-Files.

The series, based on a trilogy by Blake Crouch, has a seemingly simple set-up. Random people, except for an overrepresentation of federal agents such as protagonist Ethan Burke (Matt Dillon), are in car crashes. They awaken in a spooky hospital in a creepy little town in Idaho. Walls (thankfully not a dome), festooned with signs warning that to leave is to die, contain the befuddled but curiously unquestioning townsfolk.

Occasionally, at night, everyone’s landline rings at the same time. This is a “reckoning,” a call to gather in a central square where a throat is slashed for a minor transgression. Graffiti-ing a wall. Mentioning life before Wayward Pines.

The kids – “generation one” – attend an academy run by a headmistress who looks and sounds just like Lisa Kudrow from Friends. I expected her to sing Smelly Cat before realizing she’s really Hope Davis, and terrifyingly manipulative.

When people try to escape the walled town, murderous ghouls flit by and the people vanish.

Idaho_regions_mapSPOILER ALERT!

The phone calls drawing people to reckonings remind me of H.G. Wells’s classic The Time Machine. Its future humanity diverges into the above-ground meek, sleek, blond and blue-eyed Eloi and the dark and dangerous subterranean Morlocks. When the Morlocks are hungry, they sound a siren. The happy Eloi, in a trance, march right into their dens, doomed to become dinner.

But the Wayward Pines gatherings are to prevent being eaten.

After the first 4 episodes, I was certain that Wayward Pines was a resting place for spies, like The Prisoner, another short summer TV series, from 1967. The Prisoner followed a British spy who had just resigned, who’s abducted and sent to a weird, walled prison-like community. I was wrong, and the reveal in episode 5, “The Truth,” knocked me off the couch.

The year is 4028, and the residents of Wayward Pines are all that’s left of humanity, unless pockets of survivors exist (a second season might explore this). Our descendants have become, due to genetic mutations as yet unspecified, “aberrations,” aka “Abbies,” which Wikipedia accurately calls “violent humanoid predators.” Episode 8 ends and 9 begins as an Abbie devours an unfortunate escapee just a few feet outside the walls. In contrast, the Morlocks’ hunting was implied; the 1960 film that scared the crap out of me didn’t actually show the carnage, just the aftermath.

4028? A mere two millennia for humanity to wipe itself out and a new hominin species come to dominate?

128px-Brown,r_time_macine60The dual humanity of The Time Machine, a not-so-subtle allegory of British class distinctions in the early twentieth century, was plausible because the Time Traveler in his contraption zaps ahead to the year 802,701. That’s enough time for geographically separating gene pools with a sprinkling of mutations, plus natural selection acting on sun versus no sun, to have sculpted the two species from one. It’s a duration reminiscent of when several species of Australopithecus co-existed with Homo habilis in Africa, the terrain and other obstacles separating groups sufficiently to allow their differences to persist. At least until our brains developed sufficiently for our forebears to invent travel and for populations to mix.

We can only conjecture how the Eloi and Morlocks branch from humanity. In Wayward Pines, the survivors can thank the mysterious David Pilcher, whose profession is perhaps mad scientist. He had an inkling, back in the 1990s, that the Abbies were coming. According to Donald Trump’s way of associating simultaneous events into causality, Pilcher’s inspiration might have been the grunge movement.

To save humanity, Dr. Pilcher abducted a bunch of people back then and froze them. But unlike Woody Allen’s Miles Monroe in Sleeper, who was frozen like a bag of peas and catapulted two centuries into the future, some of Pilcher’s guests awake in 4014, thaw, learn the truth, and violently kill themselves. So he keeps the others in the deep freeze a little longer, then plants them above his subterranean lab in Wayward Pines. This time, he doesn’t tell the defrosted followers where they are, or why. He knows they can’t handle it, but Matt Dillon disagrees.

How did Dr. Pilcher choose his founding society? Did he invoke a selection process, like in When Worlds Collide or the Twilight Zone episode in which families are chosen to board a spaceship to escape Earth’s imminent destruction?

Heston_and_harrison_planet_of_the_apesThe Abbies of 4028 may share the planet with simians, if one considers the various guises of The Planet of the Apes franchise. The 1968 film’s protagonist Taylor crash-lands in 3978, according to the smashed chronometer on his spaceship. Mark Wahlberg replaced Charlton Heston in Tim Burton’s 2001 version. Mark leaves Earth in 2029, landing on future Earth in 5021. Beneath the Planet of the Apes takes place in 3955, and the TV series in 3085.



The most recent incarnation of the Apes replaced time travel with a runamok gene therapy viral vector that only recently made pet chimp Caesar supersmart. He and his similarly doctored labmates take over within two decades, just in time for a sequel.

Darwin’s Children, another of my favorite books, makes more sense than the errant gene therapy vector and may have inspired it, Greg Bear having published it in 2003. In the world of Darwin’s Children, a retrovirus called Sheva splits humanity, endowing the infected with neurological enhancements that, presumably, will one day enable them to take over, even as discrimination against them surges.

A theoretical way that the human species could diverge rapidly involves a type of chromosome aberration called a Robertsonian translocation. Two different acrosomes – chromosomes with one long arm and one very short arm, numbers 13, 14, 15, 21, and 22 – attach, yielding at first a carrier with one smushed together unusual chromosome, and if carriers mate, some individuals with 44 rather than the normal 46 chromosomes. Without delving into the intricacies of meiosis, the people with 44 chromosomes could not produce viable offspring with the 46-ers and so would technically be an instant separate species, should they decide to procreate. Case Report: Potential Speciation in Humans Involving Robertsonian Translocations details how this can happen. Robertsonian translocations have led to speciation events in rodents and sheep.

But back to the peculiar little town in rural Idaho.



The humans and Abbies apparently diverge over about 134 generations, figuring 30 years as a generation time. That’s about the number of fruit fly generations I tortured as a graduate student. Not really long enough to generate a new species.

So here’s one scenario of the origin and evolution of the Abbies from us. I’m borrowing from other science fiction plots, but notably omitting being impregnated by a space alien and giving birth to a humanoid who looks like Michael Jackson with sparkling eyes and a revved up libido, as happens to Halle Berry’s astronaut character Molly Woods in CBS’s Extant.

1. Something kills a lot of people so the founding Abbie mutations can reasonably become a significant proportion of the population. I suggest a fast-acting flu, as in the terrific new book Station Eleven. The flu decimates about 99.9% of the human population, from 7 billion to 7 million.

2. A massive environmental disaster dismantles infrastructure, like in The Day After Tomorrow. Waves of earthquakes and tornadoes throw up great dust clouds that usher in an extended nuclear winter, as in Robert McCammon’s glorious Swan Song (from 1987, my all-time favorite apocalyptic novel).

3. The prolonged darkness, over time, topples food webs, killing off many species, thereby seeding the eventual cannibalism of the Abbies. Actually, we don’t know if they are a different species because so far they’ve eaten people, not had sex with them. So it might be just hunting.

4. A nice population bottleneck whittles the number of survivors even further, narrowing the gene pool in a random fashion. Then genetic drift, a consequence of sampling from the long-gone whole, and positive natural selection acting on advantageous traits, amplify the impact of certain gene variants.

5. Generations pass. Recessive mutations find themselves paired in individuals, bringing novel traits and new diseases. Meanwhile, new dominant mutations act faster than recessive ones, a point we’ll return to shortly.

6. Nonrandom mating might spread a mutation that offers a survival advantage.


Imagine a settlement of 200 or so people who have survived all the disasters. A boy, let’s call him Adam, has undergone a de novo (i.e. new, not inherited from his parents) autosomal dominant mutation that makes him gorgeous, strong, smart, very horny, and very aggressive. Perhaps Adam has a dominant mutation in a gene that confers “central precocious puberty,” which in Online Mendelian Inheritance in Man, the bible of geneticists, brings “conduct and behavior disorders” in addition to accelerated sexual maturity.

Armadillo-Florida-crop-2009The first mutant to have a lasting impact will be a male, because like Tom the bull who inseminated thousands of cows and Genghis Khan, who famously spread his Y chromosome throughout the world, males can parent more children in a lifetime than females. Then couple Adam and his mutation with Eves prone to ovulating more than one egg at a time, or perhaps even a female capable of conceiving identical quadruplets, like armadillos. The Abbie mutation and other gene variants on its chromosome (transmitted together thanks to linkage disequilibrium) spread through the fledgling population.

Within a few generations, dominant homozygotes arise in whom a dosage effect intensifies the phenotype. As more disasters and plagues ratchet down the biodiversity, the hungry and ever-more aggressive Abbies begin to eat the terrified last remnants of humanity.

Except the residents of Wayward Pines – until tonight, when the walls come down.

Please share your hypotheses!

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