Sequencing Kids’ Exomes: More Good News

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1000 genomeExome” hasn’t yet entered the normal lexicon, like genome has. Yesterday, for example, I wore my clinical exome T-shirt from Ambry Genetics to Zumba class, and a woman came up and peered at my chest.

“What the heck is that? What are all those letters? And what’s that little gap? A misprint?”

So I explained to the class what an exome is, and that no, my shirt had a small deletion, not a fabric defect.

Within 5 years, though, I think people will know what an exome is, because analyzing it will be as common as a CBC or blood lipid profile is today before visiting the doc. As costs decrease and gene discoveries increase, we’ve reached a tipping point, by definition when “a series of small changes or incidents becomes significant enough to cause a larger, more important change.”

Until “exome” becomes a household world, clever studies are illuminating pioneering applications of the technology.

The exome, the part of the genome that encodes protein, harbors 85% of disease-causing gene variants (we’re not supposed to say “mutation” anymore, but that’s what I mean). Results from several large studies have been published over the past 3 years, but a paper in last week’s Science Translational Medicine from Stephen Kingsmore’s group at Children’s Mercy–Kansas City offers the most promising results yet.

dna“It heralds the dawning of the new age of clinical genetics. We’ve been waiting for this to come around for 10 to 15 years, and it’s finally here,” says Robert Marion, MD, chief of the division of genetics at The Children’s Hospital at Montefiore and a  developmental pediatrician at the Albert Einstein College of Medicine, about the paper (he’s not part of the team). I devoured his book “Genetic-Rounds: A Doctor’s Encounters in the Field that Revolutionized-Medicine.”

Last month, the Journal of the American Medical Association published findings of two ongoing prospective exome sequencing studies of individuals with symptoms suggesting an inherited condition. A group from UCLA diagnosed 213 of 814 (26%) cases that hadn’t been diagnosed clinically or with single-gene tests or panels. The 26% rose to 31% if parents had their exomes sequenced too. The second report, from Baylor College of Medicine, diagnosed 504 of 2000 (25.2%) patients. Both studies weren’t just children.

I wrote in Medscape about the Baylor team’s interim results presented at the American Society of Human Genetics annual meeting in November 2012. At the same time I pitched the story to a top science magazine, whose editors had no idea what I was talking about. Now lots of magazines run kid exome stories. (I’ve a long history of being too-soon with biotech stories.)

By late 2012 the Baylor team had analyzed 300 exomes, with a 25% diagnosis rate. Most interesting to me, as always, were the cases. They reported several that illustrate two scenarios in which exome sequencing shines: a 2-year-old had Marfan syndrome but not the usual long limbs (“atypical presentation”), and a 9-year-old boy actually had two genetic diseases (“co-morbidities”).

Both boys were treated, once physicians knew what to treat. That also happened with the Children’s Mercy–Kansas City study that achieved a “molecular diagnosis” for 45% of their 100 families. They set up their study to extract a ton of information.

The more recent higher percentage – 45% compared to 25% — might be because the Children’s Mercy group considered only neurodevelopmental disorders (which include developmental delay, autism, and intellectual disability). By comparing newborns in intensive care units to older children who are veterans of multi-year “diagnostic odysseys,” the study revealed the great value of early exome sequencing. And they showed that the technology is cheaper and faster than a gene-by-gene approach.

Cifrão_symbol.svgCOSTS CONVERGE
When it comes to genetic testing, more is indeed better. Finally.

It’s been clear that exome and even genome sequencing would eventually cost less than single-gene tests ever since Myriad Genetics began charging $3,200+ for sequencing just the two BRCA genes. The new study homes in on the converging costs.

The investigation began at Children’s Mercy 3 years ago when the Center for Pediatric Genomic Medicine formed. “This is a retrospective look at the first 100 families enrolled in the genome center repository for diagnosis of neurodevelopmental disabilities,” Sarah Soden, MD, a developmental pediatrician and first author of the paper, told me. The 119 kids of those first 100 families had symptoms that didn’t exactly match those of any of the 2,400 or so known single-gene nervous system conditions.

Given my non-existent math skills I appreciate the cut-off at 100 families. Fifteen of the families had children hospitalized in the neonatal or pediatric ICU, and the rest were veterans of the average 7-year trek to diagnosis. The acutely-ill 15% had their genomes sequenced too, because exome sequencing can miss genes buried in GC-rich genome regions, which confound DNA replication enzymes like a stutter disrupts speech. Illumina provided instruments that can sequence genomes in under 50 hours, although analyzing the data takes a few days.



Considering the kids by the direness of their clinical situation proved telling. Genome sequencing diagnosed 11 of 15 (73%) of the families with kids in the ICU, while exome sequencing diagnosed 34 of 85 (40%) of the families with older children. The older kids were less likely to be diagnosed because their years of testing had ruled out many illnesses.

And that previous testing was expensive: on average $19,100 per nonacute family. The researchers estimate that sequencing would be cost-effective at up to $7,640 per family. Plus, there’s no metric for diagnosis of a child that takes days rather than years.

Of the 119 children, 18 had many symptoms because they had two genetic diseases. Five young patients had been receiving the wrong treatment, which was stopped, and 12 were treated correctly following accurate molecular diagnosis. So exome/genome sequencing isn’t only informational, it’s practical.

My favorite parts of exome and genome sequencing papers are the cases, as well as those I learn about when seeking comments for articles in Medscape. That happened when I talked recently with Dr. Marion, who says exome sequencing is already routine in clinical genetics.

“Our group had been following a family for 6 years, and they’d had every test that could be imagined. High-resolution chromosome testing, FISH, single gene mutation analysis for specific disorders — everything normal. The child had growth retardation, developmental delay, and multiple congenital anomalies,” he told me.

The parents, first cousins, knew that if the condition was inherited, they were carriers and every child would face a 1 in 4 risk. Dr. Marion sent a blood sample from the 6-year-old to have his exome sequenced just when the couple had become pregnant again.

“We found a mutation in a gene we’d considered (H syndrome), but the child didn’t fit completely. We then tested the fetus and unfortunately it was affected,” Dr. Marion continues. The parents ended the pregnancy because they felt they couldn’t care for two children with the condition, and appreciated the information. Only 50 cases of H syndrome have been reported.

Sequencing the exomes of parent-child trios, like in the syndrome H family, is especially informative because if the parents don’t have mutations that could cause the condition, then their child probably has a new and dominant mutation. And that means it’s unlikely to repeat in a sibling.

Dr. Soden describes a child in the Children’s Mercy trial who also “didn’t fit.” He had autism, up to 30 seizures a day, and by age 3 had a tremor and difficulty walking. By 10 he was wheelchair bound. A series of photos in the paper show his initially beautiful face becoming slightly skewed as he grew, a common finding in inherited conditions.

“This patient had gone years without diagnosis and enrolled for whole exome sequencing, with his parents. That identified a mutation in the PIGA gene that has historically been associated with a blood disease, but had very recently been associated with neurologic disability in infants. All patients described had passed away before a year of age, and this kid was 10 at the time,” Dr. Soden says. Pyridoxine (vitamin B6) has helped children with similar syndromes, so maybe it will help him.

The new study shows that exome sequencing can reverse the diagnostic trajectory, going from genotype to phenotype. Dr. Soden loves it. “What’s so exciting about genomic medicine is the practical side. Diagnosing the patient provides answers to families and physicians, and at the same time we can make discoveries.”

But Dr. Marion waxes wistful about handing over the excitement of the hunt to the precise new tool that is exome sequencing.

Dr. Marion with a young patient. (Children's Hospital at Montefiore)

Dr. Marion with a young patient. (Children’s Hospital at Montefiore)

“The bad part for me, being a cranky old clinical geneticist, is that it takes out of our hands the art of clinical genetics. In the old days we’d look at a child and analyze the information and come up with a differential diagnosis that might include 3 or 4 disorders. We’d go through the list, ruling out diagnoses. Now we recognize a kid has multiple congenital anomalies and send off samples for testing and get answers and try to fit the kid into the identified condition. But it’s definitely worth the benefit to families, siblings and patients.” Dr. Marion has solved many such mysteries in his career. In the photo he’s with a patient, now a teen, whose genetic disease (mucopolysaccharidosis type VI) he could name just by looking at her, followed up with genetic testing of course.

Although studies from Baylor, UCLA, Children’s Mercy, the NIH’s Undiagnosed Diseases Program, and others have certainly validated exome (and back-up genome) sequencing, it might be a few more years until the neighborhood nurse practitioner or urgent care physician pops a patient’s sample into a sequencer before venturing a diagnosis. “People trained more than 5 to 10 years ago have no idea how to use this information and will have to be retrained to do so,” says Dr. Marion. Medical schools are educating future physicians  in genomics.

Sarah Soden, MD (Children's Mercy-Kansas City)

Sarah Soden, MD (Children’s Mercy-Kansas City)

Dr. Soden expects to see exome sequencing enter subspecialty care first, and Children’s Mercy is helping with the education effort. “We have a genomic medicine master class where physicians spend a week with us and really learn what genome medicine is all about. Broad applications may be down the road, but in a center like ours we’re going to see it faster,“ she says. And Illumina holds regular workshops for health care providers to have their own genomes sequenced and interpreted, to learn the potential for diagnosing their patients.

Exome sequencing could be done on newborn heelstick blood samples.

Exome sequencing could be done on newborn heelstick blood samples.

Dr. Marion suggests another way that exome sequencing may nudge into the medical mainstream. “There’s going to be pressure on state labs to offer this in newborns. It will come from industry, because they will market directly to pregnant women: ‘Send blood from the newborn and we’ll predict the child’s health for the rest of his or her life.’ State labs will then say, ‘we have a 2-tiered system in which families that can pay get better screening’ and state health departments will say ‘we have to fix that.’ Babies will go home from the hospital and pediatricians will get readouts from the state lab of every polymorphism and mutation and predict what the person’s health will be like.”

It’ll be like cord blood storage.

But Kevin Davies, PhD, author of “The $1,000 Genome” and publisher of Chemical & Engineering News, tempers exome excitement.

“Even newborn genome screening becomes more and more plausible as the cost of sequencing continues to drop, we still await definitive evidence that this makes medical sense. I’m thrilled by the wondrous stories of diagnostic odysseys ending thanks to genome screening, but we need more than intermittent anecdotal reports to judge the clinical benefits. Trials are underway to address this key question. I also think the genetics community has a massive task ahead to communicate the benefits of genome screening to a general public that is still nervous, skeptical and even afraid of losing their genomic privacy.”


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James Watson On “Genetic Losers”

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640px-James_D_Watson_Genome_ImageI’m thrilled that Christie’s decided to auction off James Watson’s Nobel prize on a Thursday, DNA Science posting day! I’ve got some great quotes to add to the chatter.

Dr. Watson shared the Nobel prize with Francis Crick in 1962 for deducing and describing the three-dimensional structure of DNA, assembling clues from the experimental findings of many others. He went on to launch the human genome project at the National Institutes of Health, and is today Chancellor Emeritus of the Cold Spring Harbor Laboratory.

But Dr. Watson is also known for outrageous comments that insult anyone with dark skin, a fondness for the same sex, mental illness, a genetic disease, or two X chromosomes. Laura Helmuth excellently summarizes some of his comments at Slate.

(Dept. of Energy)

(Dept. of Energy)

I first heard Dr. Watson speak when I was in grad school, and too sleep-deprived to remember anything. Shortly after Francis Crick died in 2004, I decided to interview Dr. Watson while he was still around. So I spent 14 hours on Amtrak during a single day going from Schenectady, New York to Cold Spring Harbor Laboratory on Long Island, when I was writing for The Scientist. He was prompt, polite, and charming. And then I asked my first question.

“Dr. Watson, which do you think was more significant, deducing the structure of DNA, or sequencing the human genome?”

He sat back, smiled, and stroked his chin, seemingly deep in thought. It wasn’t a bad question to start. A pause, then …

“Ricki, do you consider yourself a girl or a woman?”

I never could get him to answer questions about science seriously, and I wonder now if that’s why I can’t find my piece at The Scientist website. I might have killed the story, which was to be a Q+A, before my editor had a chance to do so. And his comments were too misfired to make it into my human genetics textbook.

Maclyn McCarty, Francis Crick, and James Watson

Maclyn McCarty, Francis Crick, and James Watson

I heard Dr. Watson again at the opening session of the 12th International Congress of Human Genetics in Montreal in October, 2011. He was on a panel of “genome pioneers” who were among the first to be sequenced. Kevin Davies, author of “The $1,000 Genome  and presently publisher of Chemical & Engineering News, moderated.

Dr. Watson, who was the second to have his genome sequenced following Craig Venter, spoke first. I published a cleaned-up version soon after the conference, but yesterday found the offensive comments I’d left out earlier. They’re included in the Q and A below. Colleagues tell me they heard the “genetic losers” remarks at other conferences, but the statements don’t seem to be showing up in the news coverage, which as usual continually recycles the same info.

Watson the guinea pig

Watson the guinea pig

(Disclosure: I had guinea pigs named Watson and Crick, and Watson was one of the smartest and longest-lived pets I ever had.)

PS: At the end of the panel discussion three years ago, I was the first to leap onstage to approach Dr. Watson, to ask him to review my soon-to-be-published gene therapy book. I was very dressed up (rare for me) and the only XX in the immediate vicinity. Hoards of young, XY groupies glared up at me from the audience as Dr. Watson turned on the charm and talked to me for nearly 5 minutes. I was clearly no longer a girl. But I sent him a galley of my book and he never responded.

So here are Kevin Davies’ questions, offending answers included amongst some very useful observations, as posed to Dr. Watson at the Congress of Human Genetics in Montreal in October, 2011. (Dr. Davies in CAPs, Dr. Watson in italics, me in non-italics.)

“I thought, why not? I had no objection, with the exception of not wanting to know ApoE4. My grandmother had Alzheimer’s in her 90s, and the fact that I was in my 70s and didn’t have it didn’t reassure me I wouldn’t in my 90s.”

(ApoE4 and the surrounding DNA were deleted from Watson’s  published genome sequence. At the time people with two copies of a variant of this gene were thought to have a 15-fold increased risk of Alzheimer’s and people with one copy a 3-fold increased risk. However recent studies have found that the increase only applies to women and inheriting variants in other genes can counteract effects of ApoE4.)

“Finding that I am a slow metabolizer of antipsychotics and beta blockers. I have a slightly irregular heartbeat and the doctor put me on beta blockers. Two put me to sleep. Now I take them once a week, so knowing I’m a slow metabolizer was a real medical benefit. It also may have explained a mystery concerning my son. He almost died of neuroleptic malignant syndrome from an antipsychotic. I now know that if I go psychotic, I will tell people I can’t take those drugs.”

“They told me I had something that should have killed me, a mutation in a DNA repair gene. And so I decided not to think about it. I didn’t go and look it up. Then they told me I was one base pair off the bad one. They told me I was a carrier for BRCA1 and so I thought I would have to phone my nieces because their mother had breast cancer. But before that I asked Mary-Claire King (who discovered the gene) and she said no, I had a harmless variant. So I’m glad I didn’t call my nieces because then they would have paid that disgraceful sum of money to Myriad Genetics.”

(Jonathan Bailey, NHGRI)

(Jonathan Bailey, NHGRI)

“I’d like to see children who have mental illness sequenced with their parents. My son has schizophrenia. The moment you have a son who is not normal, you wonder if you are the cause, or if you could have done something differently. Finding a mutation would make parents see that it was just genetic injustice, not anything they did. Knowing that won’t make their child healthy, but they won’t have the double whammy of thinking they did something wrong. I think an educated society doesn’t like genetics because it is so deterministic, and they would prefer it if you could have diets so you wouldn’t have a mentally ill child.

It is my belief that about 5% of children are born with rather bleak long-term futures. They really won’t be able to take care of themselves. They might become homeless later in life and I think making people aware of this goes back to Hermann Muller who worried about mutational load. We should think this way again.

Evolution means mutations and there are going to be losers who, 20,000 years ago, would not have lived very long. But now in our so-called compassionate society we should take care of them, but we do so very badly as they age. There are some born losers. It’s not that their parents were bad. But what’s the ethical responsibility to take care of the genetic losers? Having set up the ELSI (The Ethical, Legal and Social Implications) research program, I suspect that all the programs put together have yielded nothing of value. They’re talking about minor things. The major issue is, what do we do with people with mad genes? That’s never discussed.”

James Watson and Sydney Brenner at the Asilomar conference in 1975, where recombinant DNA research was born. (Natl Library of Medicine)

James Watson and Sydney Brenner at the Asilomar conference in 1975, where recombinant DNA research was born. (Natl Library of Medicine)

“My son would say yes, but he didn’t want to. He doesn’t want to discuss it. I would have a completely different view, that we might be able to help him and he should have no choice, but that is the sort of thing brought up at ELSI meetings. I find them counterproductive to help the people born with genetic disease.

I’m very conscious of genetic losers – other people want to deny their existence. Other people want to cure them.”

“I’m more worried that we’ll get the flood of information and we won’t use it because of excessive concern about privacy. Right now I’d be pragmatic, be as free as possible with sequencing genomes, and then if disaster is the result, we’ll try to correct it. I’d hate for anyone to say ‘you can’t tell your child that he has a DNA change.’ I think parents, within limits, should have control over what their children know, and trying to regulate that would be just awful.

I’m very happy the $1000 genome exists. Genetics will help us to understand why people don’t fit in. Every time someone goes into a children’s hospital with a serious disease, it would be immoral NOT to sequence him.”

ATCG's Image with Group of PeopleIronically, this week Stephen Kingsmore’s group at Children’s Mercy-Kansas City report in Science Translational Medicine on 100 families for whom exome and genome sequencing led to diagnosis of children with hard-to-classify neurodevelopmental disorders, which include autism, intellectual disability, and developmental delay. I’ll cover this paradigm-shifting paper next week.

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Nailing a New Niche of Stem Cells

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Green highlights the stem cell niche of a mouse's nail. (Kobielak lab)

Green highlights the stem cell niche of a mouse’s nail. (Kobielak lab)

If my mother-in-law hadn’t just yanked off a toenail, I might not have noticed the news release from researchers at the University of Southern California’s Stem Cell Regenerative Medicine Initiative. Their elegant experiments in mice reveal the heretofore unknown collection of stem cells that enable the rodents, and presumably us, to regrow our nails.

Krzysztof Kobielak and colleagues (first authors are Yvonne Leung and Eve Kandyba) report their findings in the October 21 Proceedings of the National Academy of Sciences. It is unfortunately behind a paywall, so I will enlighten you.

Nails, skin and its glands, and hairs descend from the same layer of the embryo, the ectoderm. The nail is the last to reveal its stem cell secrets. Skin renews constantly, hair cycles every few months, and sweat glands don’t replace cells often if at all. A nail is the only ectodermal derivative able to completely regenerate if ripped totally out, as my mother-in-law just did.

It turns out that a nice niche of stem cells enables nails to regrow. This, to me, is the most fascinating part of stem cell science – discovering new aspects of anatomy and physiology, especially how parts initially form or regenerate.

A mouse's rear. (credit: Artie the Cat Lewis)

A mouse’s rear. (credit: Artie the Cat Lewis)

The researchers created transgenic mice that had DNA sequences encoding:
• A keratin, expressed in the ectodermal derivatives
• Green fluorescent protein (GFP) from jellyfish, a standard way to track cells
• A protein that confers resistance to tetracycline antibiotics

The genetically modified mice had skin, nails, hair, and sweat glands that initially glowed greenly. But after a bit of development, and then a course of doxycycline, the color faded in all but the stem cells, which retained the GFP marker because unlike other types of nearby cells, being stem cells they didn’t readily divide. (The color became diluted as neighboring cells divided without further stimulation to express GFP.)

The stem cells form a distinctive ring in an area of a nail called the proximal fold, the bit of nail/skin boundary just underneath the tip. The investigators named the cells “nail proximal fold stem cells.” Production of keratin #15 distinguishes the stem cells, a little like hair colors. (Most types of mammals have about 50 keratin genes.)



To see how a nail regenerates following damage, the investigators induced “nail plucking injury,” presumably under non-torture conditions, and watched what happened. That meant a transcriptional profile, a look at the messenger RNAs made as the nail regrows, and compared profiles of healthy nails as well as in surrounding skin for both situations.

A lot goes on in nails. Hundreds of genes blink on and off, just to keep nails growing normally. As expected, transcriptional profiles change following injury. After subtractions eliminated housekeeping gene expression, two genes that regulate bone morphogenetic protein (BMP), called Bambi and Decorin, emerged as the controls of nail growth. Normally they dampen production of BMP, which favors growth of the skin around the nails. But whack off a nail and expression of these genes, and of the BMP that they control, increases.

So the stem cells can do two things: favor skin, or favor nail. And they can change what they do to suit environmental circumstance.

To test the findings further, the researchers bred mice that couldn’t make much BMP. And the animals had puny nails, especially at the tips, with overgrowth of surrounding skin.

The maimed mice regenerated their nails in just 2 weeks. I imagine things will move at a slower pace for my mother-in-law.

As for most stem cell discoveries, knowing about nail proximal fold stem cells inspires the imagination.

• Understanding the signaling behind the shift from making-skin to making-nail may suggest new drug targets and candidates for assisting regeneration of human fingertips. Humans can regenerate fingers, but in a limited way compared to, say, the abilities of a starfish.

• Stem cells likely control shifts in repair at other bodily tissue interfaces. Perhaps we can tweak them, too, in therapeutic ways.

Jesse James was a famous bankrobber. DNA testing confirmed that the body in his grave was likely his.

Jesse James was a famous bankrobber. DNA testing confirmed that the body in his grave was likely his.

• Identifying the dead. Stem cells might protect DNA in a corpse, compared to a cell that normally divides often. Sampling stem cells from nails to confirm the identity of a corpse might be easier than obtaining other tissues. I’m thinking of the fuss over the DNA extracted from teeth and hair of outlaw Jesse James and the pelvic bone from 5300-year-old  Ötzi the Tyrolean Iceman.

• Cosmetic possibilities. Might a coating of BMP-spiked color or hardener halt nail growth, preserving the perfect pedicure?

200px-Stem_cell_division_and_differentiation.svgDEFINING STEM CELLS
Finding an accessible stem cell niche, even in a structure as seemingly non-vital as a toenail, is important, because tweaking the fates of any stem cells’ daughter cells might provide therapeutic cells tailored to the individual. Imagine bolstering a failing heart with cells from one’s nails.

Media gripe: many articles still define stem cells as “turning into any cell typ,” No need for links, just google that phrase.

If stem cells turned into “any cell type,” they’d soon be depleted. Rather, when a stem cell divides, it produces another stem cell (“self renewal”) and also gives rise to daughter cells that may go on, perhaps dividing more, to specialize.

The biological significance of a stem cell is the ability to perpetuate its stemness. In the illustration above, only the cells ringed in purple are stem cells.

Sweetsgiving_Feast_SpreadAn analogy. If turkey, dried bread hunks, butter, celery, potatoes, green beans, mushroom soup and other Thanksgiving fare spontaneously assembled into casseroles and such, and people ate it all, there’d be nothing left for seconds or thirds unless the fridge magically filled with more of the basic ingredients. Like the gobbled up Thanksgiving feast, an organ that uses up its stem cells and must grow to stay alive is in trouble. And that’s why stem cell science is so exciting — it uses our body’s natural reserves.

OK, so I’m not great with analogies. Have a happy Thanksgiving, and thanks to all readers of DNA Science!

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When Mutation Counters Infection: From Sickle Cell to Ebola

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Brass_scales_with_flat_trays_balanced While pharmaceutical companies focus on drug discovery for Ebola virus disease, a powerful clue is coming from a rare “Jewish genetic disease” that destroys the brain. People with Niemann-Pick C1 disease can’t get Ebola, adding to the list of disease pairs that arise from a fascinating form of natural selection.

Balanced polymorphism, aka heterozygote advantage, is a terrific illustration of ongoing evolution. And it pits the human body against all sorts of invaders – prions, viruses, bacteria, protozoa, and fungi.

sickleThe textbook example of balanced polymorphism is the protection that being a carrier for sickle cell disease confers against malaria, published in 1954.

The blood of a person with full-blown sickle cell disease is too thick to accommodate the malaria parasite, and the red blood cells too bent to house them. A carrier has enough sickled cells to quell the parasite, but not enough to block circulation and cause the pain and anemia of the inherited disease. Alpha thalassemia, hemoglobin C and G6PD deficiency are other single-gene diseases that affect red blood cells in ways that lower risk of malaria.

The link between genetic disease and Ebola virus disease dates from 2011, when Thijn Brummelkamp, PhD and co-workers, at the Whitehead Institute for Biomedical Research, reported in Nature that cells of people with the rare single-gene Niemann-Pick C1 disease keep out Ebola.

Ebola virus particles (NHGRI)

Ebola virus particles (NHGRI)

The gene that is mutant in Niemann-Pick C1 disease encodes a transporter protein that normally binds cholesterol — and it’s also the receptor for Ebola virus. Carriers of the inherited disease, with half the normal number of transporters, might have some protection against the viral disease. (A recent article in the Wall Street Journal discusses the carrier situation, but doesn’t cite the standard sickle cell example – commenters did.)

The tango between us and our pathogens is more complex than examples within ourselves of conditions canceling each other out. The poor clotting of hemophilia shields against dangerous blood clotting; the extremely low serum cholesterol level of Smith-Lemli-Opitz syndrome, which causes intellectual disability and a host of strange birth defects, counters cardiovascular disease. These don’t involve a second party.

Examples of balanced polymorphism are like mystery stories, beginning with the clue of why a seemingly harmful recessive genetic disease hangs around. New mutation is one answer, but more common is the protection that the heterozygous state offers. Here are some of the stories.

CFTR ion channel, open and blocked

CFTR ion channel, open and blocked

In cholera a bacterial toxin opens chloride channels in small intestine cells, and salt and water pour out in a torrent of diarrhea. The misfolded CFTR protein behind many cases of cystic fibrosis, which is a chloride channel, does the opposite, failing to reach the cell surface and trapping salt and water inside cells, drying secretions. A person with misfolded CFTR won’t get cholera, while a CF carrier, with enough working chloride channels to breathe okay, but not enough to welcome toxin-spewing pathogens, suffers neither disease.

The cholera epidemics that have swept through human history favored individuals who carry or have CF. But geography and history suggest that the story goes farther back, because CF arose in western Europe and cholera in Africa. Perhaps a different diarrheal infection, typhoid fever, triggered the initial favoring of mutant CF alleles that perhaps arose from mutation.

The bacterium behind typhoid fever, Salmonella typhi, enters small intestine cells through CFTR channels. In people with severe CF the channels are too mangled to reach the cell surface. Bacteria can’t enter. Cells of CF carriers only let in a few bacteria. Protection against infections that produce the runs may therefore have kept CF around.

The Guthrie test began the era of newborn screening -- half a century ago.

The Guthrie test began the era of newborn screening — half a century ago.

Testing for phenylketonuria – PKU – ushered in the era of newborn screening with the Guthrie test, invented in 1957 and one of my favorite genetics stories. It tests blood from a newborn’s heel so that dietary intervention can prevent the profound intellectual disability of the disease.

PKU is a classic “inborn error of metabolism.” A missing enzyme causes the amino acid phenylalanine to build up, devastating the nervous system. Carriers have excess phenylalanine — not enough to damage their brains, but enough to counter the effects of a fungal poison called ochratoxin A that causes spontaneous abortion.

In 1986, PKU guru L. I. Woolf published a brief letter in the American Journal of Human Genetics explaining how a fungus could maintain a rare inherited disease of humans. Ochratoxin A is a derivative of phenylalanine that binds to the enzyme that places phenylalanine into proteins as they form. With one of the 20 amino acid types blocked from joining proteins, the embryo quickly stops developing – unless the pregnant woman’s body makes excess phenylalanine, which counters the effects of the toxin. That happens in PKU carriers. Thanks to newborn screening PKU is caught early enough today to be treated, but ochratoxin causes a kidney disease in Eastern Europe called Balkan endemic nephropathy.

Ochratoxin on moldy grain altered genetic history

Ochratoxin A on moldy grain altered genetic history

It isn’t coincidence that PKU is most prevalent in Ireland and Scotland. In the dampness of those lands, the Aspergillis and Penicillium fungi that produce the toxin grow on grains, which people were forced to eat during times of famine. Because pregnant PKU carriers were more likely to have healthy children than non-carriers, who suffered miscarriage due to the fungal toxin, the PKU mutation increased in the population. That’s natural selection. Evolution. It happens.

Prions are proteins that can fold into infectious forms that cause transmissible spongiform encephalopathies. The most familiar are those that come from eating the proteins, such as mad cow disease. The classic example is kuru, which caused brain degeneration among the Foré people in Papua New Guinea in women and children eating the brains of honored dead relatives. The Australian government halted the practice in the mid-1950s.

But we also make our own prion protein – the gene that encodes it is on chromosome 20. Normal prion protein is abundant in the brain, and likely plays a role in synaptic plasticity in early development. This story is more complicated than those of Ebola, CF, and PKU, because the same protein comes from inside and outside the body, and it is the protein, in abnormal form, that is the pathogen. Prion protein is a shape-shifter, able to assume the infectious form right inside ourselves.

Back to New Guinea. Some of the female Foré brain eaters are still alive, and an investigation of the prion protein gene among 30 of them revealed that 23 are heterozygotes for the prion protein gene on chromosome 20, meaning that they have two slightly different versions of the gene. Population genetics statistics predicted only 15 of them should have been so.

The carriers have the amino acid valine at amino acid position 129 on one chromosome 20 and a methionine on the other. And this somehow prevents the infectious misfolding. Plus, everyone in the UK who developed mad cow disease had only methionine at position 129.

And so cannibalism may have fueled the overrepresentation of carriers of the infectious form of prion protein. Protected, the carriers slowly accumulated in the population.

Brass_scales_with_flat_trays_balancedWHY IT MATTERS
For many years, the central dogma reigned, the idea that DNA encodes RNA which encodes protein. Our genomes were thought to encode protein, and do nothing else, although people hypothesized vague “controls” amongst our regular genes.

Then introns (non-protein-encoding parts of genes) came along in 1977 and turned our simplistic view on its head. Most of us in genetics never thought the “rest” of the genome was “junk.” If I remember correctly, that was an unfortunate utterance from Francis Crick that the media ran with, and it stuck.

Today we know that the human genome comes complete with all manner of controls. Some are indeed embedded in the non-protein encoding sequences that make up most of the genome. Other controls are in short RNAs that fold themselves up in ways that glom onto and turn off certain genes, and in the numbers of short repeated sequences that pepper genomes. The human genome is a little like a fancy TV with a zillion remotes that somehow knows how to control itself without the user knowing how it all works.

Balanced polymorphism is yet another form of genetic information. It reveals a story, a subtext to our genes written by our own actions throughout history, and the scourges that felled some of our ancestors, enabling individuals carrying particular mutations to survive to reproduce, perpetuating those mutations.

Making sense of the intriguing pairings of genetic and infectious diseases can reveal ways to fight those infections. Let’s hope this approach works for Ebola virus disease.

(Parts of this post are based on passages in my textbook, Human Genetics: Concepts and Applications (Amazon doesn’t yet list the new, 11th, edition). For each edition I struggle to limit myself to 2 examples of balanced polymorphism. It is difficult to choose!)

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Eman Reports From Ebola Ground Zero

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The arrow shows Emmanuel Gokpolu at an awareness meeting in Monrovia.

The arrow shows Emmanuel Gokpolu at an awareness meeting in Monrovia.

The last post here at DNA Science continued Emmanuel Gokpolu’s reporting from Ebola ground zero in Monrovia, and surrounding communities. The Ebola outbreak interrupted Eman’s medical education, so now he is teaching his people about strategies to minimize risk of infection. Eman and I began a very special friendship when he contacted me when using my human genetics textbook in college, years ago.

This post of Eman’s emails picks up in early October. That was when Ebola jumped overnight from a topic rarely reported in the U.S., to major news once it had, perhaps inevitably, arrived here. My questions are in italics.

Eman, what is your reaction to the belated response among many in the US to Ebola’s spread?

I read some comments on CNN about the outbreak in Africa, and it was disgusting. I didn’t believe humans could be so unsympathetic. I earmarked a few:

“Africans are uncivilized, so they always get infected by some sh..t.”

“Stop those barbarians from coming to America immediately.”

“Why is our government spending our taxes on those c _ nts?” and so forth.

I’m not happy that it’s in the US, but I’m sure it will change some perceptions.

In the US infected patients are isolated and given supportive care immediately, experimental drugs when possible. What is the situation in Liberia?

A man posts a list of rules of how to prevent spread of Ebola.

A man posts a list of rules of how to prevent spread of Ebola.

Considering our traditional practices of bathing the dead at home, monkey and bushmeat as delicacies, our weak healthcare system and day-to-day interactions, I always thought this virus could spread at an incredible rate. Not enough has been done to curb the spread. Hundreds of homes do not even have buckets for washing hands. In fact, the health systems have not been reinforced to deal with seasonal diseases like diarrhea and cholera and this has led to many deaths.

Our own governments are at fault too! Imagine, our government set up an Ebola response team without a medical practitioner on board; not even a medical student. Isn’t that absurd?! Others have made it a money-eating (corruption) show; $100,000 USD meant for tracking cases gets missing and even donated buckets get sold. America alone is not to blame.

How are you using your medical and communication skills?

I have been busy with Ebola workshops this week. I chair a youth organization called “Determined Youth for Progress” that has been working a lot sensitizing communities about Ebola prevention. We luckily got a grant to carry out more sensitizing and buy more buckets and chlorine (bleach) for distribution.

We will also be doing virus contact tracing (people will be tasked with identifying people who may have come into contact with sufferers). We will also be sending out short text messages every morning to tell family and friends about the virus:

“Dear friend,
You have received this text because I’m well. I’m well because I follow the rules. Please do the same: wash your hands regularly, do not touch sick people rather, report them to health authorities by calling 4455.”

We also want to look into tutoring kids at their homes because schools are closed, and creating awareness messages through short poems.

Getting funding is always difficult, but our volunteers have been great! Tomorrow, we carry out a big community clean-up. We’re on Facebook: Determined Youth for Progress (One post: “Ebola is everybody’s business. Let’s spread the message.”)

3 ebolaOCTOBER 21
Should exposed individuals in the U.S. use public transportation? Subways? Cruise ships? Planes? Bicycles?

People should know how dangerous the virus is. Allowing infected persons to be in crowded places, on cruise ships, or in planes poses greater risk to others.

I believe we can win the fight against Ebola from the level of community involvement. Everyone must cooperate in some way to win this fight, especially in listening to the experts.


Is the epidemic abating?
There are signs that progress is being made in battling the epidemic, but we have been telling people to stick with the rules, to avoid newer cases. For example, I was in Bomi County yesterday and found out that there were seven cases handled for a week with nothing new coming. The number of cases per week is gradually reducing and we remain hopeful that we can turn the tide in a few months.

The New York Times recently reported that fewer Ebola cases are in hospitals. What does this mean?

Most hospitals are closed. This has made the situation even more difficult. There are cases where people died because of no access to hospitals. This in part is due to the shortage of PPEs (Personal Protective Equipment). Health workers are afraid to treat even the simplest of conditions due to this. All cases are being handled by the ETU (Ebola Treatment Units).

4How is your community work progressing?
I have been busy with the community organization I chair (Determined Youth for Progress), organizing Ebola awareness workshops, sensitizing rural communities on the prevention and spread of the virus, and working with bigger organizations like the Gbowee Peace Foundation Africa to get grant support for our projects. It’s been really challenging, but we are making progress. We have been able to reach a lot of rural communities and the reports we get from there show that we made an impact.

Quarantine is a highly contentious issue in the U.S. Do you think it is necessary?

It’s sad that people returning from Africa think they are being stigmatized by being quarantined. I think the intention is to avoid another outbreak. It’s a little sticky for me to discuss because someone might say Africans don’t know what civil liberty really is because most often, our leaders seize them. lol.

If it is in any way stopping people from volunteering to curb the outbreak, they should consider doing the quarantine in the country where the person worked before coming to the U.S. That is, if Mr. X worked in Guinea and decided to go back, he should be quarantined in Guinea before going back to the US. Health workers must also understand that it is for the safety of their family and friends that they have been subjected to such methods. As harsh as it might seem, if nothing of such is done, they might pose a threat to others.

5 lecture againWhat have you learned from the current Ebola situation?
Basically, the epidemic has exposed our weak healthcare systems and taught us how dangerous it is to underestimate disease outbreaks.

Ebola has been much more devastating compared to other outbreaks like cholera, malaria and typhoid in such a short period of time. It has broken families and held countries under siege. The world needs to take this as an example and be on the alert.

Thanks so much, Eman. Be well.

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Eman’s Emails from Liberia: Through September

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Emmanuel Gokpolu and son Larry, from Liberia.

Eman Gokpolu and son Larry, from Liberia.

Emmanuel Gokpolu, who lives in Liberia, calls me Mom, although he has a wonderful real mother. In Africa, family isn’t only about DNA.

Eman contacted me in 2007, after using my human genetics textbook in college. My husband Larry and I had been putting him through medical school in Monrovia — until Ebola happened. Now the funds go for gloves, long sleeve shirts, detergents, food and medicine, to keep Eman and his family, including his almost-one-year-old son, little Larry, safe.

This week Eman asked me to share his emails, which began arriving before many people here had heard of Ebola, or cared much about it if they had. Then the disease seemed, and was, half a world away.

The world is a small place.


“Hi Mom and Dad, hope all is well with you. It’s not that good here. The Ebola virus has everyone living in fear. One of our professors, a doctor, died from the virus yesterday. Imagine? So much fear. Please keep us in your meditations. Your son

These have been some of the worst days we have witnessed.

Public facilities and gatherings have been discouraged, schools have been closed, some marketplaces and even clinics closed just to curb the incursion of this virus. Worst of all, some heartless people have been poisoning pumps and wells.

Medical students have only been used to sensitize communities on the outbreak and prevention. There was not much we could do due to lack of medical supplies. This virus mostly affects health workers and caregivers.

We could have done much better to stop this virus from killing so many people if not for denial that the virus exists. You won’t believe this: in the midst of all these deaths, people still doubt that this virus exists! In fact, people are blaming the West, while others say it’s government propaganda. Others are even claiming that health workers are deliberately killing people to extract body organs.

Family members and loved ones do not easily accept when their relatives are diagnosed. People consider the virus more a stigma than a sickness.

As a medical student Eman can't treat people, so he is a  "sensitizer," educating people on how to avoid infection.

As a medical student Eman can’t treat people, so he is a “sensitizer,” educating people on how to avoid infection.

I’ve been working with a local organization that I chair to sensitize people in my community. It’s been a huge job with little material to work with but overall, it’s been great.

The family is fine and we are all keeping safe. It’s only Larry that has not been doing that well. He got sick, been vomiting, red eyes and high temperature. We got so afraid and had to call the Ebola response unit because these are all signs and symptoms of the virus. We are relieved that he’s negative and is being treated.

Hugs, Eman


Ebola is on the rise day by day. The death toll keeps mounting. President Sirleaf has declared a 90-day state of emergency.

Fear of the virus has prompted many hospital workers to abandon clinics – many are now shut. Because of this, many diseases like typhoid and malaria that are prevalent during the rainy season are untreated and there could be preventable deaths. We are living in fear.

Public transport vehicles have been ordered to reduce the number of passengers. Also, physical contact sports have suspended all practices and games, but more awareness needs to be done. During my organization’s community awareness campaigns, we noticed that some people hardly even know of the virus. Unhealthy practices that might spread the virus are still done.

Basically, the message here is to wash our hands as often as possible. Go to public places and you will see buckets with chlorinated water to wash your hands before entering.

Mom, this situation is very serious and the outside world might not know it.

(Wikimedia Commons)

(Wikimedia Commons)

AUGUST 10 (I tried to interest editors in Eman’s story, but got resounding rejection. This is his response to news of my failure.)

Tell them that our hospitals have closed due to their inability to tackle this virus, that even our medical doctors and nurses have fallen to this virus, and that our schools are closed and we live under a state of emergency, meaning our rights are suspended. Above all, tell them that we lack the experts to conquer this virus. Make them understand that this is no fiction or fairy tale. This is reality and people are dying and desperately need help.

(I quoted a short Eman email here mid-August, because media reports were so oversimplified, mixing up RNA and DNA, genome sequences and genetic code, that I felt I had to spell out the science, in “How Ebola Kills.”)

Two of my ex high school mates have died of the Ebola virus as have nurses from St. Joseph Catholic hospital. This hospital has been hit the hardest with more than 6 health workers dead from the virus and 10 more positive. It just doesn’t get better. More needs to be done, I keep saying. Our health system is just too weak for this outbreak. It was too weak before the outbreak.

The state of emergency has made things tough. The prices of food have skyrocketed and if something is not done, it might be another emergency! The health authorities have put into place measures to curb the spread of the virus but the cases keep coming. Among these measures are:

• Every business has chlorinated water in buckets outside for washing hands for those entering. This includes banks, churches etc.
• Schools are closed indefinitely
• Taxis are only allowed three persons in the back.
• Checkpoints have been set up to control the movement of people.

Sadly, there has been no decrease in the number of cases. My family has decided to send the younger kids up country to our mom where they will be monitored. Also, due to the increase in food prices, we have to reduce the number of people. Food is in short supply. We have heard that health experts are coming from the US and Nigeria, but none yet.

Sonn and grandson (4)AUGUST 12

I am using a phone to email you. Public gatherings are not encouraged, so I don’t see an Internet cafe as safe.

I just lost my elementary health science teacher to Ebola. It hurts so much. We can’t give up though.

Today, another Ebola case made health workers abandon an entire clinic. Two patients in critical condition were taken to the Goodwill clinic. Upon finding out they had Ebola, the workers escaped. This shows how unequipped and unprepared our health workers are to tackle this outbreak. Also, families knowingly keep love ones in their homes attempting to treat them, infecting themselves.

A friend from my community went to Guinea to visit his family before the outbreak. His father got infected and died and his mother and two sisters are infected too and seriously ill. He doesn’t know if he’s infected. He called today and broke down in tears. This is so scary!

The ZMapp is here and will be given to two doctors. Other health workers’ families have to sign that they acknowledge that it is a trial drug and might have unknown side effects which, if it occurs, will not hold the company or government responsible.

eman and flagsFrom a personal perspective, I have a few doubts. Why didn’t the US government present this trial drug until two of its citizens got infected? Why hasn’t anyone tried the serums of those who survived the virus? WHO says there are only 12 doses. What happens after those 12? Lots of questions in my mind.

Seeing loved ones die with no options to save them is just so ridiculous! I wish I could do something to help. Just staying safe at the moment. Survival is cardinal right now.


I know we have got you worried but I must tell you that it is more than you see on TV. Everyone is so, so afraid! From the way this situation has been handled, I fear for the worst. Would you imagine that there is a single burial team to dispose of Ebola-related dead bodies? As a result, people are exposed day in, day out. In fact, there are only a few isolation centers, making them overcrowded. This government is joking with our lives.

With the millions coming in as aid, we should be somewhere but the situation is becoming even worse. If I had a voice, I would recommend that aid be sent through NGOs instead of the government.

An Ebola quarantine site was attacked and looted, and most of the patients have escaped. This is going to put more fear into the population. All of this is happening because people are denying the virus. Keep me in your meditations.

Ebola_virionsAUGUST 18
Need help!

(Eman developed fever and pain. Relieved that it was “just” hookworms and malaria, he was hospitalized for a week.)

There’s some not very good news. The virus has struck on the street where I live; the physician from a clinic in my area. That makes it very, very scary. In spite of that, I applied to volunteer with MSF. Still awaiting their call. I only fear for the community because this is going to be my daily routine when I’m a doctor. We all have to help now, but maybe in a safe way.

Mom, You have to pray for us harder. Things are getting worse by the day; more than 1300 deaths and thousands more infected. WHO projects even more terrible times. We just don’t know what to do.

Supplies might not take us through the 90 days as prices have gone the highest. Larry is running out of food, and his medications too. We all have to take preventive malaria pills in case we encounter mosquitoes. Even worse, all quarantines are over capacity and new patients are told to go home. Quarantines are out of food and beds. It’s a nightmare!

We just can’t wait to see those troops on the ground. They have to be fast before we all perish!

little LarryThe economy is crashing. Importers have stopped importing basic commodities. Milk and medicines for babies are so expensive. Basic goods prices have doubled or tripled, especially drugs. The syrups for Larry, once opened, cannot be used more than a week because we do not have the means to store them for long, so we have to spend huge sums buying the same drugs. His milk was $22; it’s now $35. If something is not done quickly, there is sure going to be a food crisis.


School is closed indefinitely but I have to keep reading and researching. I have been following the Ebola virus and vaccine trial closely. I’ve read a lot of articles on the virus and mutations it is undergoing. I hope it doesn’t become airborne; just one of many possibilities. Keeping it safe. Hugs. Eman”

SEPTEMBER 30 (me again)

Ebola arrived in the US with Thomas Eric Duncan, visiting from Liberia. He showed up at Texas Presbyterian Hospital in Dallas, where some of the medical staff appeared not to know how to keep viruses out of one’s body.

ebola deathsAs the U.S. finally began to wake up and my inbox overflow with reports on Ebola, I began emailing Eman everything I received, even the embargoed news releases and papers available only to journalists. His need to know all he could was insatiable, and the ignorance here has stunned both of us. I continue to find scientific errors both in hurried reports to clinicians as well as in the top magazines. (Vanity Fair’s “Hell in the Hot Zone,” by Jeffrey E. Stern in September, is a notable exception — it’s terrific.)

STEM education, anyone?

Emmanuel Gokpolu, medical student and community organizer at the epicenter of the Ebola epidemic, who has lived with cholera and cerebral malaria and amoebiasis, can tell westerners a thing or two about this virus.

Eman’s story will continue next week, picking up at the start of October — a turning point here, but just another horrific day in Liberia.

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Another Reason Freezing Employees’ Eggs is a Terrible Idea

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Graafian_Follicle,_Human_Ovary_(3595010317)Facebook and Apple’s decision to offer female employees a $20,000 benefit to freeze their eggs indicates a stunning disregard for the complexities of reproductive biology.

The Center for Genetics and Society issued a news release that listed societal, technological, and biological concerns: the danger of freezing eggs to both the woman and the individual that may one day arise from that egg, and adverse effects that include infertility, cancer, and even death. I’m recovering now from surgery to remove an 18-pound ovarian cyst, so I’m especially sensitive to tinkering with ovaries in any way.

Marcy Darnovsky, PhD, executive director of the Center for Genetics and Society, summed up the bigger picture beautifully, which deals with intent, not biology: “Why are Facebook and Apple endorsing a technique that encourages their employees to put their health at risk? Paying for egg freezing is being presented as a benefit for women, but it may be that discouraging women from balancing work and family is really a benefit to the companies.”

Trisomy 18

Trisomy 18

I’d like to add another layer to the discussion: we just don’t know that much about WHY older eggs tend to end up with a wrong number of chromosomes. A terrific recent research report in the American Journal of Human Genetics addresses exactly this issue: how do older eggs mis-sort their chromosomes? I wonder if the egg-freezing advocates at Facebook and Apple read it.

I always felt weird, as a genetic counselor, telling a woman older than 35 that she was of “advanced maternal age.” But back in the days of amnio, before non-invasive prenatal testing became available circa 2012, we did indeed consider these women high-risk.

The maternal age effect for trisomy 21 Down syndrome

The maternal age effect for trisomy 21 Down syndrome

The “maternal age effect” is real: ovulating eggs with extra or missing chromosomes (aneuploidy) does happen more frequently as a woman ages. The risk of a woman carrying a trisomic fetus is 2 to 3% if she’s in her twenties, but exceeds 30% if she’s in her forties.

But the advice of who should have amnio was more technological than biological: At age 35, the risk of aneuploidy matched the risk of amnio being followed by miscarriage. Younger than that, in the absence of a family history of aneuploidy, the risk of the procedure outweighs the risk of the problem. Although amnio risks fell precipitously over the years, for some reason that age of 35 remained a standard.

In my textbooks and classes, I’d flippantly call the phenomenon the “rotten egg theory,” but it’s technically termed the “production-line hypothesis,” an idea first hatched in 1968 by Alan Henderson and Robert Edwards, who pioneered in vitro fertilization. The hypothesis states that the oocytes that have been hanging around in the ovary the longest accumulate the most errors.

As my cyst, named Waldo, grew this past summer, I had plenty of opportunities to ponder the mysterious biology of the human ovary. The male of the species, not surprisingly, is simpler: he begins manufacturing sperm at puberty and continues to do so throughout life, without a monthly reminder of the process. A female starts making eggs when she herself is a 5-month fetus. That means a pregnant woman holds the future eggs that could become her granddaughters.

Just before birth, a female has a million or so eggs stopped at a stage of meiosis (the form of cell division that makes gametes) when the two chromosomes of each pair tend to wrap around each other and exchange parts, a little like two people hugging and trading hats and belts. Apparently, this crossing over is very important for the ability of each chromosome pair to disperse into separate cells as division continues.

700px-Order_of_changes_in_ovary.svgAn ovary housing developing eggs does indeed look like a production line, with baby eggs enlarging and developing as they reach the periphery. An ovary is a little like a bag of microwave popcorn.

By puberty, about 400,000 eggies remain in a woman’s two ovaries. Each month, a few eggs awaken and take a few more steps in meiosis, halting at the very brink of chromosome pair separation, like 23 pairs of aligned square dancers. At the mid-cycle hormone surge, the biggest egg pops out.

Ovulation! The lucky female cell drops into the waving arms of a waiting Fallopian tube and moves towards the uterus.

If a blast of sperm arrives and one dude penetrates the egg’s membrane, the female cell, finally, finishes up meiosis. The egg then concentrates most of itself – cytoplasm, organelles, nutrients — into one daughter cell, along with exactly one copy of each chromosome type. The puny other cell, a polar body, exits the body, its function to siphon off the second chromosome set while concentrating supplies for the fertilized egg. Unless probed in a genetic test, as a previous post described, the polar body is flushed out.

If the egg escapes a sperm’s penetration, it too exits as the menstrual flow, meiosis unfinished. The female cycle may make us crampy and crabby, but biologically speaking, it is most elegant and not at all wasteful, only completing meiosis when it makes sense to do so.

In the study reported in July, Terry Hassold, PhD, from Washington State University and colleagues took a closer look at events in the human fetal ovary. And they discovered that one assumption of the production line hypothesis, that the oldest eggs cross over less and that’s why they may drop or add a chromosome, simply isn’t true.

The researchers used immunofluorescence microscopy to label proteins that mark crossovers, examining 8,518 cells from 191 samples from ovaries removed at 14 to 26 weeks of gestation. The material came from  elective abortions.

Results were surprising, considering how entrenched the production line idea was.

The extent of crossing over varied, not greatly, between ovaries and even within ovaries. More importantly, the researchers found no correlation between age of either the egg or the woman and the extent of crossing over.

“If the production-line hypothesis were true, you’d expect lots of abnormal cells and you would expect them all to be happening late. We do see a pretty high incidence of abnormal cells, but they’re just as likely to be happening early as late,” first author and doctoral candidate Ross Rowsey told WSU News. The effect might not have shown up in earlier studies that inferred crossing over from cells taken after birth because that approach didn’t look at what was going on in fetal ovaries.

The beauty of scientific inquiry, as I pointed out last week, is that when one hypothesis is disproven, investigators follow another. And in the case of the misjudged eggs, another possible explanation is that the reason for an extra or missing chromosome is ebbing levels with age of a protein called cohesin that, as the spellcheck-confounding name implies, glues chromosomes together, facilitating the exchanging of parts. Experiments from other species are now pursuing the cohesin hypothesis.

The bigger picture is that Facebook and Apple are attempting to pay female employees to undergo a very risky procedure with not-well-understood consequences, when we don’t even know the mechanism behind the maternal age effect. Hasn’t the current Ebola crisis taught us not to ignore biology?

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SCID-X1 Gene Therapy, Take 2

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Like the mythical Phoenix, gene therapy for SCID-X1 has risen from its ashes.

Like the mythical Phoenix, gene therapy for SCID-X1 has risen from its ashes.

Beneath all the bad news about viruses this week lies a good virus: the one that underlies gene therapy for X-linked severe combined immunodeficiency (SCID-X1).

Altered viruses are the vehicles that transfer healthy human genes into the cells of people in whom the genes aren’t working, providing a slew of new “forever fixes.” Nearly 100 gene transfer protocols are now in late-stage clinical trials.

The long-anticipated research report in the New England Journal of Medicine sets gene therapy back on track, after a previous clinical trial treated the disease but triggered leukemia. The ongoing saga is also a terrific example of how scientific inquiry catalyzes medical progress.


SCID-X1 became widely known as “bubble boy disease” in 1976, when John Travolta played David Vetter in the film “The Boy In The Plastic Bubble.” It was a year after he rocketed to fame as sweathog Vinnie Barbarino on the TV program “Welcome Back Kotter.”

David Vetter lived in a spacesuit when outside his bubble. (NASA)

David Vetter lived in a spacesuit when outside his bubble. (NASA)

David Vetter was born at a hospital in Texas in 1971 and was immediately placed into a habitrail-like apparatus. His parents knew a son would have a 50:50 chance of inheriting the condition because they’d already lost a newborn to it.

For years, David wanted out of the bubble. The doctors let that happen when he was 13, to receive his sister’s bone marrow in an attempt to cure his immune deficiency. But David succumbed within weeks to lymphoma seeded by the Epstein-Barr virus in her donated cells.

By 1993, researchers better understood the disease. SCID-X1 impairs the gamma chain of the interleukin-2 receptor (IL2RG), which triggers an immune system shut-down: first T cells and natural killer cells, then B cells, so that the body makes neither cytokines nor antibodies.

“Because IL2RG is needed for many cytokine receptors and immune cell development, kids die of viral infections in a year,” said David Williams, MD, chief of the division of hematology/oncology and director of translational research, Boston Children’s Hospital, at the American Society of Gene and Cell Therapy annual meeting last May where he discussed interim trial results.


With the mechanism so well understood and a clear route through the bloodstream, gene therapy for SCID-X1 seemed obvious, especially because it had already been underway for another form of SCID, ADA deficiency, since 1990. Gene therapy for SCID-X1 could help children who do not have a bone marrow donor.

A Trojan horse is a metaphor for gene therapy. An engineered viral vector  is the horse.

A Trojan horse is a metaphor for gene therapy. An engineered viral vector is the horse.

Alain Fischer, MD, PhD, of the Necker Hospital for Sick Children in Paris and colleagues conducted mouse experiments in 1994, applied to begin clinical trials by 1997, and by 1999, the first boy, an 8-month-old, received his own bone marrow cells carrying healthy SCID-X1 genes, delivered in a retroviral vector. The team waited until the April 18, 2002, New England Journal of Medicine to publish results on the first 5 children treated, to allow enough time to track building immunity.

In the months after the paper came out, one of the boys developed a swollen liver and spleen, and his white blood cell count began to climb. By summer’s end, blood tests clearly indicated leukemia.

It was exquisitely bad timing.

The gene therapy community was still reeling from the death of 18-year-old Jesse Gelsinger in 1999, from gene therapy for a very different disorder. Although 18 of the 20 boys given the gene therapy for SCID-X1 established immunity, 5 developed leukemia, and one would ultimately die from it.


In the fall of 2002, when only one boy had leukemia, it seemed a family history of cancer or recent chickenpox infection might have been at fault. But then a second boy developed leukemia. By October 2003, the research team nailed the culprit: the vector had integrated into an oncogene called LMO2.

Retroviruses normally home to very active genes, oncogenes among them. But the vector used in the first-attempt SCID-X1 gene therapy included DNA sequences that enhanced the oncogene’s activity, revving up cell division.

And so an international team (including besides Boston Children’s and the Necker Hospital, also Great Ormond Street Hospital, Cincinnati Children’s Hospital Medical Center and UCLA Mattel Children’s Hospital) began again, in what several researchers at the gene therapy meeting in May called a “do-over.”

In the second go-round, the viral controls were replaced with DNA sequences strong enough to make enough of the errant IL2RG gene, but less likely, if able at all, to ramp up oncogene action. The new breed of viral vectors now used in gene therapy are comfortingly termed “self-inactivating,” or SIN.

This time, so far, the gene therapy for SCID-X1 is effective and safe. Seven of 9 boys treated with the new vector have regained immunity, without developing leukemia. Times since treatment range from 16 to 43 months, with a median of 33 months. But because leukemia took up to 5 ½ years to show up in the first study, the current group of boys will be followed for 15 years.

For this second trial, the researchers tracked where the vectors inserted into the boys’ genomes. Compared to the trajectories of the first-generation vectors, the retooled ones seemed to avoid 21 regions that house cancer-associated genes.

Gene therapy for metachromatic leukodystrophy uses lentivirus to the brain. It works too. (Gunter Pusch)

Gene therapy for metachromatic leukodystrophy uses lentivirus to the brain. It works too. (Gunter Pusch)

As work continues on the retroviral approach to treating SCID-X1, a third-generation vector is in the works too. A team at NIH is using SIN lentivirus (disabled and engineered HIV) that doesn’t home to the LMO2 oncogene. It’s being tested on young adults whose transplants have lost effectiveness, with promising results so far.

Success for the ADA deficiency form of SCID is on track too. “More than 50 patients have been treated by gene therapy between trials in Italy, the UK and our trials in the US in the past decade and a half. None have had complications from the gene transfer and most have successful immune reconstitution,” says Donald Kohn, MD, from UCLA and a co-author on this week’s NEJM.

For ADA-SCID, gene therapy “is becoming the treatment of choice for patients lacking a matched sibling donor, surpassing the alternatives of a matched unrelated donor or a half-matched parent donor, and far less costly than ongoing ADA enzyme replacement therapy,” Dr. Kohn adds. Transplants also bring the risk of tissue rejection and graft-versus-host disease.


The ongoing SCID-X1 story illustrates several broader aspects of biomedical research that are often lost in media coverage.

• “Breakthroughs” aren’t usually news, but can reflect decades of work by hundreds of researchers. Teams include undergrads, grad students, technicians, and post-docs, not just the prizewinners or those with the most Twitter followers or TED talks.

• Progress reports are often presented at scientific and medical meetings, and if the media attend, articles follow (although researchers don’t always realize this). That’s why the headlines and endless repetition of press releases via aggregators following publication in a major journal can seem like echoes. They are.

600px-Flat_Earth_Society_Logo• “Scientific proof” doesn’t exist. Every result sparks new questions, and no conclusion is ever final, for what we learn continually teaches us how much more we need to know. If science ever had a final word on something, we’d still think the Earth was flat, that proteins are the genetic material, and that the entire human genome encodes protein.

Dr. Kohn elegantly sums up the significance of the SCID-X1 gene therapy trial results reported this week:

“It’s a reflection of the iterative bench-to-bedside process, with initial clinical observations spurring further research studies and a next generation of treatments brought to the clinic. For this specific disease, SCID-X1, this study represents a do-over in using the indisputable logic of gene therapy to treat this most responsive disorder, using prior lessons to do it even better.”

(The history of SCID-X1 is covered more fully in my book The Forever Fix: Gene Therapy and the Boy Who Saved It.)

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No Ice Buckets or Pink Ribbons for Very Rare Genetic Diseases

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Max Randell, left, has Canavan disease. His brother Alex is going to be a neuroscientist.

Max Randell, left, has Canavan disease. His brother Alex is going to be a neuroscientist.

As enthusiasm for dumping ice on one another fades with autumn and October brings pervasive pink, I wish that attention would turn to families confronting diseases not as well known as ALS and breast cancer.


According to the  National Organization for Rare Disorders, “rare disease” in the U.S. means affecting fewer than 200,000 people. These conditions number about 6,800, collectively affecting nearly 30 million Americans or 1 in 10 people.

Many rare conditions are single-gene diseases. That means that the chance of more than one family member being affected is quite high (see Mendel’s first law). Unlike those, most (>90%) cases of ALS and breast cancer aren’t inherited as single-gene traits, but are sporadic. Mutations happen during a person’s lifetime in somatic (b0dy) cells, perhaps due to an environmental trigger. A family with sporadic ALS wouldn’t have to worry too much about the patient having passed it to a child; not so a family with Huntington disease. IMG_0831

With many causes of rare diseases, comparing statistics is an apples-and-oranges exercise. But I collected a few anyway, for prevalence (the percentage of a population with a particular disease at a given time).

Breast cancer (all types) affects 122 in 100,000 people. ALS (all types) affects  3.9 per 100,000. Absolute numbers are more meaningful for the rarest of the rare. For example fewer than 100 people worldwide are known to have giant axonal neuropathy, which is similar to ALS in a young child. But unlike ALS, the chance of a sibling of an affected child also inheriting the condition is 1 in 4. Thanks to exome sequencing, even “one-of-a-kind” individuals with strange constellations of symptoms that defy shoehorning into known diagnoses are being understood. The exome kids are tantalizing to journalists (see the New Yorker.)

But so very many diseases aren’t chosen for the New Yorker, or don’t have a Lou Gehrig or Joan Lunden materialize. Doing_the_ALS_Ice_Bucket_Challenge_(14927191426)


I had mixed feelings about the ice bucket challenge (henceforth “IBC”) for ALS, noting how few people have read my posts here about the disease, compared to important posts like how Dan Brown screwed up genetics in his latest bestseller. So I polled the rare disease families I know about the IBC, and boy did I strike a nerve! They share awe at the brilliance of it, joy at how much was raised for ALS, surprise, and a bit of envy.

“People associated with other diseases became really upset, probably because they wished they had thought of it. It took on a life of its own, and then it just abruptly stopped when people became tired of watching endless videos, and that caused a backlash,” said Ilyce Randell, president and co-founder of Canavan Research Illinois. The organization’s major annual fundraiser celebrates son Max’s birthday — he’ll turn 17 later this month. I’ve been to two of them. (Canavan prevalence: about 10 in 100,000.) This post chronicled Max’s brother Alex’s efforts to fight brain disease.

Laura and Taylor, in happier and healthier times.

Laura and Taylor, in happier and healthier times.

Laura King Edwards is running races in all 50 states to raise awareness and funds for infantile Batten disease, which has robbed her 16-year-old sister Taylor of her sight, mobility, speech, and ability to eat. Laura took the IBC and attempted to extend its reach.

“I did try to post some more educational/advocacy-related links on the Taylor’s Tale Facebook and Twitter pages. Those posts didn’t get much response. People didn’t want information with meat to it – they wanted to watch entertaining videos of their friends. That’s where our challenge comes in – how to identify strategies that are sustainable. Because if I know anything, it’s that the fight against rare disease won’t be won overnight,” she said. (Prevalence of all forms of Batten disease is  2 to 4 of every 100,000).


The IBC seemed to have gotten under the skin, in one way or another, of nearly everyone I contacted.

“We didn’t pay much attention to it, and did not accept the challenge from anyone. We kept the focus on our goal,” said Jennifer Pletcher, whose daughter Finley has Leber congenital amaurosis (LCA) caused by mutation in the RDH12 gene. “Some people actually did the challenge and donated to our foundation, which was cool,” she added, pointing out that October is Blindness Awareness month too. See (Prevalence of her daughter’s condition: 10% of the 2-3 per 100,000 who have any of the 22 genetic forms of LCA.)


Ilyce Randell echoes Jennifer Pletcher’s focus on her family’s disease. This isn’t being selfish, it’s using genetic logic. While rare disease umbrella organizations are enormously helpful in sharing information and strategies, funding clinical trials is a different matter.

Testing a treatment for a single-gene disease requires participants who share mutations in the same gene. Finley Pletcher’s LCA is due to mutation in a different gene than the one that is mutant in Corey Haas, the boy at the heart of my book The Forever Fix. His successful gene therapy targeted his RPE65 gene.

Campaigning to treat all forms of LCA, or all forms of Batten disease, is useful in addressing shared concerns, but might dilute the financial power needed to get a phase 1/2 clinical trial off the ground, or support the daunting cost of a phase 3 trial necessary for FDA approval for marketing.

“Fundraising/awareness campaigns are more effective when we do not try to unite every similar disease. Parents of children affected by Canavan who raise money and direct it to a blanket organization are often times not helping advance research for their own child. We’re raising money for the only researcher who has ever worked with living Canavan patients in a clinical setting. But there are families raising money for ’research’ for ‘allied diseases,’ organizations that do not even fund her work. When it comes to curing my son I’m not in a true alliance with any other disease because all funding is scarce, and different diseases are competing for the same federal funds,” shared Ilyce.

And that competition is fierce. Just two days ago, the U.S. Food and Drug Administration (FDA) announced “awards of 15 grants worth more than $19 million to boost the development of medical device, drug, and biological products for patients with rare diseases.” Six are going to cancers, 2 to infectious diseases, 4 to others that aren’t inherited, and of the 3 that are, two are for sickle cell disease and one for cystic fibrosis – classic textbook genetic diseases. “You have an easier time asking for money for something people have heard of,” said Ilyce. SavingEliza - instagram

Glenn O’Neill is more enthusiastic about the IBC, perhaps because his family’s efforts to “save Eliza” from Sanfilippo syndrome also went viral, before the ice buckets descended . They adapted the “challenge” part of the ice bucket craze.

“On August 12th we started our #Sing2Lines to stop Sanfilippo challenge based on Eliza’s love of music and the fact that she can still sing. You post a video of yourself singing 2 lines of any song, and challenge 5 friends, to give Eliza and other children a voice, and a chance at life,” Glenn said.

They’ve sung their way to more than $75,000 with thousands of entries, including one from actress Andie MacDowell.

128px-Emoji_u1f4b0.svgPAYING FUNDRAISERS

For the rarest of the rare, fundraising efforts are usually family-run, all volunteer. This is not often the case for more common conditions. When any disease organization calls for a donation, it’s a good idea to ask how much of what you donate actually goes to research or patient support. Check out Charity Navigator.

A caller for a large breast cancer organization had the misfortune of getting my husband on the phone last October. Larry volunteers for several not-for-profits that do not pay fundraisers or anyone else, and he immediately interrupted the script to ask whether said organization paid the people who made the phone calls. Yes, they did.

But breast cancer is so common! You must know someone who has it!” insisted the paid caller.

If it’s so common, why can’t you get volunteers to make the phone calls?” Larry asked.

Laura King Edwards weighed in with “Pink for One Heck of a Price Tag” two years ago, noting that the NFL shelled out $5 million on ads and paraphernalia for their breast cancer awareness blitz. “If I could write a $5 million check to the world’s best Batten disease experts, I believe in my heart that they’d give us a treatment that works,” she wrote.

Others chimed in on the cost of fundraising issue. “For Finley’s Fighters, 100% goes to research. We don’t have overhead cost or paid employees. We rely on sponsors for our events and all other costs come out of the family’s pockets,” said Jennifer Pletcher.

Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.

Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.

Kristin Smedley, who has two sons with the CRB1 form of LCA, agrees. “I let my supporters know that our fundraising does not pay salaries, it does not pay for office space, it does not pay for public relations firms to get me on TV. We are all volunteers here working out of our kitchens.”

Their annual event, Bike the Basin, raises enough funds to sponsor an annual research meeting for their CRB1 (Curing Retinal Blindness) Foundation– I attended the first one.

I’m not insensitive to the challenges of cancer. I had it. And I watched my mother undergo treatment for metastatic breast cancer. But an entire month of “raising awareness” for breast cancer? Who, exactly, hasn’t heard of it? And who is being ignored as a result?


Of all of the inspiring rare disease family members I’ve “met” during my writing journeys, the most spellbinding is Jacey Mukka. She turns 22 later this month; she didn’t think she’d live past 21.

Jacey has juvenile Huntington disease (JHD). With prevalence 5% of the adult version’s 5.7 cases per 100,000, there isn’t much interest. lists only one trial, from the European Huntington’s Disease Network, that tracks kids who have symptoms, rather than still-healthy at-risk individuals who’ve inherited the mutation. For another apples-to-oranges comparison, I entered “glioma,” the type of brain cancer that’s just received 3 of the 15 grants from FDA, into 1,439 hits to JHD’s lone one.

Karli, Jacey's little sister.

Karli, Jacey’s little sister.

Jacey’s dad and little sister Karli passed away from HD; Jacey’s older sister has it too. Jacey is very ill, but I don’t want to dwell on her body here. Details are in another post. Instead, I’d like to share her thoughts.

I promised myself when I was younger I would die before my little sister, I would die before my father, I would die if I ever got the temper of my father or started hurting people.

But that didn’t happen. Karli died at age 13, in 2010. Jacey remembers.

Reality still hadn’t hit, until the nurse came in. She said to come say goodbye. No it’s not possible, it can’t be. I went into her room and I saw her lips were blue. Mom and Erica snuggled up to her and she took her last breath. She was free. It hurt worse then I thought ever possible, just hold her bunny and curl up on the couch and cry until you run out of tears, and cry even after that. We gave Daddy her pink rabbit and he held it as tight as he could, and then he died 2 months later.


Max, HD mascot

Jacey started after hearing families talk about having children even though a parent has the HD mutation, because “the child wouldn’t get sick until it was older and by then they’d have a cure.” Jacey sends hugs and books to the friends she’s made, and raises funds to help them get through life, one day at a time. The website is full of facts, stories, and ideas. And it is vital, if only to a few, because no one’s dumping ice to draw attention to JHD.

I wish the ice bucket challenge had brought more recognition to the hundreds of rare genetic diseases that lie so under-the-radar. Far more lasting than the ICB is Facebook, where I hear daily from my “families.” Facebook connects the individual efforts that are so important to conquering the single-gene diseases, one at a time.

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DNA and Dating: Buyer Beware

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128px-Emoji_u1f4b0.svgLast week’s post dealt with three very serious types of DNA tests. But not all DNA tests detect health-threatening conditions.

A few years ago “Born to Run? Little Ones Get Test for Sports Gene” ran on the front page of the New York Times, above an arresting image of a preschooler having his mouth swabbed for DNA. It’s from 2008, but remains a classic: I still assign it.

800px-FPYC_Soccer_-_02The sports gene company tested for variants of one gene, ACTN3. Two copies of the R577X variant indicate inborn skill at endurance events, and no copies suggest a child stick to sprints. The lucky heterozygotes might excel at both! Never mind that a child has some 20,000 or so other genes affecting physiology.

The most damage a sports gene test can do is to keep a child from something she loves because of a DNA-obsessed parent. A more questionable application of DNA testing is in “relationship science,” something I learned about a few weeks ago when a reporter from asked me about it. And so I perused the website of the “leader in human genetic compatibility.”

The company offers tests for four genes. Three are members of the human leukocyte antigen (HLA) complex, which encodes the cell-surface proteins that determine who can give body parts to whom and reflects many disease susceptibilities. The fourth gene, SLC6A4, encodes a serotonin transporter.

Both the HLA genes and SLC6A4 have been studied for decades. Yet the test panel doesn’t include ancestry markers, which I think might be more important in mate selection than tissue compatibility.

Nasonia vitripennis, mating (Elizabeth Cash and Josh Gibson)

Nasonia vitripennis, mating (Elizabeth Cash and Josh Gibson)

The company is using HLA typing as a surrogate for scent, claiming that 40% of olfaction comes from the genes. But the existence of human pheromones is still under debate, although they were predicted to exist half a century ago, and many a website will happily sell you some. (The image shows tiny wasps with the wonderful name Nasonia vitripennis mating, thanks to pheromones wafting from the male.)

More telling in the scent department may be the 1995 study of women preferring the sweaty T-shirts of men least like them genetically. Wikipedia credits it with starting the field of genetic matchmaking.

Why wouldn’t humans have pheromones, when so many other animal species do? Plus the HLA genes are so involved in biological compatibility that I suspect they indeed have something to do with scent and pheromones. But do we need a DNA test to tell us when a potential date stinks? Maybe so. That’s one characteristic we can’t yet inspect on our electronic devices.

Bone_Marrow_TransplantKnowing one’s HLA type is not without value, but its hard to say whether one should seek a mate with a different or similar profile. People with different HLA variants may be less likely to pass infections back and forth. But couples with similar variants would be better off if one of them needs a blood transfusion, bone marrow transplant, or part of a liver.

SLC6A4, which encodes a serotonin transporter, is also a logical choice for a dating gene. Like the HLA genes, its variants are associated with several health conditions: sudden infant death syndrome, Alzheimer aggression, depression following emotional trauma, alcoholism, neuroticism, deviant sexual behavior, hypertension and obsessive-compulsive disorder.

(Dr. Yoichi Araki)

(Dr. Yoichi Araki)

The SLC6A4 protein recycles the neurotransmitter serotonin to the reuptake stations on presynaptic neurons in the brain. Serotonin is what’s theoretically scarce in some cases of depression (like pheromones, that hasn’t been definitively shown either), and so the transporter provides a target for the “selective serotonin reuptake inhibitors” like Paxil. It’s also the target of the older tricyclic antidepressants, as well as amphetamines and cocaine.

People can have a short version or a long version of one part of the SLC6A4 gene. In one study, people with two short variants self-reported future dissatisfaction with their marriages if they previously reported high or low emotional behavior (whatever that means). Conversely, if people have at least one “long” version of the serotonin transporter gene, then their emotional behavior does not influence their perceived long-term stability of their marriages.

What the serotonin transporter has to do with dating is beyond me, although I have not dated in centuries. But I think a shared love of dark chocolate, running, and binge-watching Orange is the New Black may be more meaningful measures of day-to-day compatibility than SLC6A4 genotype.

Testimonials on the company’s website attest to the fact that people do believe that choosing dates based on limited genotyping has value. They are falling into the trap of genetic determinism, the idea that DNA is destiny.

Valentines_Book_1940_1“We knew the test would show a great match because we knew we had chemistry when we met. We think the test results show that the Instant Chemistry DNA test can help singles find that person who they have a real connection with,” writes one satisfied customer.

I emailed the company requesting data showing that people with particular genetic profiles are more likely to be compatible, and how the company defines and assesses compatibility. I haven’t heard back yet. However, a news release from July, prompting a flurry of media coverage, informed us that the company is “proving that there is science behind attraction,” with “new, groundbreaking research.” So stay tuned.

ATCG's Image with Group of PeoplePRECEDENTS

Using genetic testing in mate selection is a decades-old strategy. Dor Yeshorim is a program that originated in the Hasidic Jewish community in New York City. It has tested thousands of young people from all over the world for several “Jewish” genetic diseases since a rabbi who had children with Tay-Sachs disease started the program in 1983. Testing is anonymous, using numerical identifiers, and carriers are not told what they carry – just whom to avoid having children with, if they so choose. Their testimonials are the plummeting incidences of some of these diseases in the tested population.

800px-Foundation_(cosmetics)At the other end of the seriousness-of-genetic-testing spectrum, federal regulators are finally cracking down on dubious DNA-based claims. Two years ago I’m embarrassed to admit that I bought “age-defying with DNA advantage cream makeup” because I couldn’t resist the goop in the see-through container swirled into a double helix shape. I’d thought I’d read that FTC had made these genetics references in cosmetics ads disappear, but they forgot to tell Google.

Adding “DNA” to skin cream ads doesn’t really hurt anyone. But making medical claims is a different story.

My favorite study exposing misuse of genetic testing is from the U.S. Government Accountability Office, like the sports gene flurry also from 2008, when  direct-to-consumer genetic-testing debuted. GAO investigators submitted DNA samples from a 9-month-old girl and a 48-year-old man to four “nutrigenetics” companies, but with 14 made up lifestyle/dietary profiles. None of the companies, which offered dietary suggestions and pricey packages of exactly the supplements that an individual purportedly needed to avoid her or his genetic fate, bothered to do a health history.

Lo and behold, the advice from the four companies tracked with the made-up backgrounds and not genetics. And the results reported on very common conditions (to which genes may contribute minimally) and stated the obvious, like not smoking. Concluded the study: “Although these recommendations may be beneficial to consumers in that they constitute common sense health and dietary guidance, DNA analysis is not needed to generate this advice.” Some of the suggestions could even be dangerous, such as vitamin excesses in people with certain medical conditions.

640px-Snake_oil_or_Memory_Elixer_anyoneI don’t know if the FDA, FTC, or GAO are interested in a dating website that preys on those who don’t know much about DNA. My advice for deciding whom to date? Talk to people! Don’t shell out hundreds of dollars to learn about a handful of genes.

(Some of this material comes from chapter 20, Genetic Testing and Treatment, in my textbook Human Genetics: Concepts and Applications, just published by McGraw-Hill in the 11th edition.)

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