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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Genetic Testing For All: Is It Eugenics?

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ATCG's Image with Group of PeopleIn recent weeks, there’s been talk of three types of genetic testing transitioning from targeted populations to the general public: carrier screens for recessive diseases, tests for BRCA mutations, and non-invasive prenatal testing (NIPT) to spot extra chromosomes in fetuses from DNA in the maternal bloodstream.

Are these efforts the leading edge of a new eugenics movement? It might appear that way, but I think not.



When I began providing genetic counseling 30 years ago at CareNet, a large ob/gyn practice in Schenectady, NY, few patients were candidates for testing: pregnant women of “advanced maternal age” (35+), someone with a family history of a single-gene disorder or whose ethnic background was associated with higher prevalence of a specific inherited disease. Their risks justified the cost and potential dangers of the tests.

Now the picture is rapidly changing as plummeting DNA sequencing costs and improved technologies are removing economics from the equation. It’s becoming feasible to test anyone for anything – a move towards “pan-ethnic” genetic screening that counters the “sickle-cell-is-for-blacks and cystic-fibrosis-is-for-whites” mindset.

So here’s a look at three very different types of genetic tests that are poised to make the leap to the general population. And despite new targets revealed with annotation of human genomes, some of the detection technologies themselves are decades old.

Population screening for carriers of single-gene diseases has been around since those for sickle cell disease and Tay-Sachs disease in the early 1970s. We learned a lot from their starkly different results. For years, labs such as Athena Diagnostics, the Baylor College of Medicine Medical Genetics Laboratories, Emory Genetics LaboratoryAmbry GeneticsGeneDx and  others have added genetic tests to their rosters, which now cover hundreds of single-gene diseases, from A (Alport syndrome) to Z (Zellweger syndrome).

HORIZONlogo(CMYK)Other companies have recently visited CareNet, pitching tests for more single-gene diseases for everyone. For example, Natera’s Horizon Carrier Screen tests for 39 conditions and 127 variants of the cystic fibrosis (CF) gene. They provide genetic counseling by phone, which is common these days, given the scarcity of trained genetic counselors, especially outside cities. And Natera can tailor screening panels to specific populations.

In addition to the changing economics, the public is more familiar with DNA-based tests, partly due to the direct-to-consumer testing company 23andMe. Before FDA forbade them from selling carrier tests as “information,” thousands of people learned about recessive diseases from the company’s excellent website.

Cystic fibrosis illustrates the widening of test offerings. Carrier screening began in 2001 for whites and Ashkenazi Jews, following recommendations from the American Congress of Obstetrics and Gynecology and the American College of Medical Genetics. By 2005, with many more mutations identified and the diagnosis broadened, testing expanded to everyone. At CareNet every pregnant patient gets a CF test, along with a factsheet that I wrote.

counsyl-logo-largeCF is just one gene of thousands. Researchers from Counsyl, another newer player, published a key paper reporting on 23,453 patients from ob/gyn, genetics, and infertility clinics screened for 108 disorders. Nearly 24% carried at least one disease-associated recessive mutation! 5.2% (1,210) carried 2 or more, and .33% (78) actually HAD a disease by having inheriting two mutations.

Interestingly, stratifying participants by population group revealed the differences that once fueled restriction of testing. Although overall 24% of the total carried at least one disease, that ranged from 6.3% among Native Americans and 8.5% among East Asians to 47.1% among the Finns and 43.6% among Ashkenazi Jews. Only 15.8% of African-Americans were carriers.

BRCALast week in a controversial Viewpoint in JAMA Mary-Claire King and colleagues suggested “that population-based screening of women for BRCA1 and BRCA2 should become a routine part of clinical practice.” These genes normally participate in DNA repair, and mutations raise risk of several cancers, not just the widely-reported breast and ovarian. (BRCA1 mutations predispose to cancers of the cervix, colon, uterus, and pancreas, and BRCA2 to cancers of the stomach, gallbladder, pancreas and bile ducts, as well as to melanoma.)

Results from the first families that Dr. King analyzed, published in 1990, were Ashkenazi Jewish with several affected members, because it is easier to discover a gene and what it does in a population with very few variants. It turned out that this group has only three mutations, all of which obliterate the genes’ vital function. Sequencing the entire huge gene wasn’t necessary, lowering costs substantially.

Based on the 1990 paper and follow-up, for years we genetic counselors would consider the number of cases of the relevant cancers and ages at diagnosis in families. We used published guidelines to decide to whom to offer BRCA testing.



That approach invariably missed some cases in families that were small or had few female members. We knew that accruing data on populations beyond the high-risk Ashkenazim would take years, mostly because thousands of mutations exist.

Many people thought Dr. King’s suggestion of wider BRCA screening premature. Criticism centered on the experimental design in the PNAS paper that the Viewpoint addressed, also from the King group. It focused on Ashkenazim because with fewer mutations the data were easier to collect, especially back when the study began.

The researchers tested more than 8,000 healthy Ashkenazi men in Israel for BRCA1 and BRCA2 mutations, and then offered testing to all female relatives of the 175 men found to have mutations. These women, it turned out, indeed had very high risks of developing the associated cancers – and about half of them had NO family history. Following the old guidelines would have missed them. (An important caveat in the Viewpoint cautioned that testing should only be for meaningful mutations – not the many “variants of uncertain significance.”)

But we can’t know which mutations lurk in whom unless we look for them! And not testing members of families that don’t fit the original pattern will miss cases. That’s what happened in my friend’s family.

Maya’s son discovered he had a BRCA mutation after he took a 23andMe test, for fun, back when one could do this. Maya was tested next because she’s Ashkenazi, but it was her husband, who’s Catholic and European, who’d passed on the mutation to their son. Fortunately their daughter escaped the family legacy. But here’s a family in which the cancer can indeed begin in either father or son, and in more distant relatives. The affected individuals are now being tested regularly for the associated cancers – no one is running off to have organs removed. A positive genetic screen result — meaning identification of a gene variant, not a diagnosis — signals a need for vigilence and preventive health care. It’s not a ticket to surgery.

(Shendure lab)

(Shendure lab)

Until recently, testing fetal DNA (NIPT) was only advised for pregnant women at higher risk of the fetus having an extra chromosome 13, 18, or 21, the most common trisomies. That is, women over 35, or who’d had a previous trisomy. Soon it will be offered to all.

Entire fetal genomes can be sequenced from DNA snippets in the maternal bloodstream, which are shorter than the woman’s DNA pieces. But whole genomes are, for now, TMI. The first commercial non-invasive fetal DNA tests detect abnormal chromosome ratios or differences at single sites (SNPs) on those chromosomes in both genomes, in high-risk women. By August 2014, the data indicated that NIPT is safe enough for low-risk women.

At least half a dozen companies now offer NIPT. It will clearly save lives.

“The sweet spot is for women who are deciding whether or not to have an invasive procedure because they are at higher risk due to advanced maternal age, a positive screen of serum markers, or a fetal sonographic abnormality. If testing fetal DNA gives an all-clear, at least for these three chromosomal conditions, then the pregnant woman can avoid the risk of a more invasive procedure, such as amniocentesis,” Diana Bianchi, MD, professor of pediatrics at Tufts University, told me.

Dr. Bianchi  is the mother of the invention, described in this DNA Science blog post. She reported detecting cell-free fetal DNA and suggested noninvasive prenatal testing back in 1996. “Nine to one, women want the blood test first, and a great majority of them have a negative result, so they don’t go on to have amnio or CVS,” she added.

But that benefit wasn’t immediately obvious to critics unfamiliar with the spectrum of prenatal testing options. Dr. Bianchi received threats from people who saw testing fetal DNA as a way to avoid the births of people with Down syndrome and the other trisomies.

Eugenics_congress_logoIS IT EUGENICS?
Eugenics is “the science of improving a human population by controlled breeding.” Mention of the term is often followed by reference to Nazis.

Are recessive disease carrier screening, BRCA mutation testing, and NIPT eugenic, according to the definition? Only one might be, and even that’s questionable. Let’s dismiss the other two first.

BRCA testing alerts relatives to the need for active surveillance for certain cancers, for their own health. At least in my experience in counseling patients, an inherited cancer susceptibility is not a reason to keep one person from having kids with another, or to end a pregnancy, because the cancers are late-onset and treatable. Plus, a person who inherits a BRCA mutation must then undergo a second, somatic mutation in a cell in the organ that develops cancer, according to the classic two-hit mechanism. It isn’t the cancer that’s inherited, but the increased risk.

NIPT is not eugenic in its current guise because trisomies – extra chromosomes – result from mispairing in meiosis. They’re not inherited, they just happen, although a person with a trisomy is more likely to produce “unbalanced gametes” that can perpetuate the situation. But most new trisomies are spontaneous glitches that result from a chromosome pair not parting when it should as sperm or egg form.

The one type of testing that could ultimately have a eugenic effect is carrier screening for recessive diseases. The Counsyl paper concludes that “sequencing the entire genome of each patient would reveal ~10 times as many lethal recessives on average.”

Imagine including one’s personal collection of recessive mutations on a DNA dating site! (See yours truly quoted in The New Science of Matchmaking: Dating Based on Your DNA).

Natera’s description of the Horizon Carrier Screen leads potential patients through Mendel’s first law: an offspring of two carriers of the same condition faces a 25% chance of inheriting the disease. “If you find you are at risk, you can take steps to prevent having a baby with a genetic disease,” the clear explanation continues.

For couples who discover they carry mutations in the same gene, the company offers Spectrum, which uses pre-implantation genetic diagnosis (PGD) to choose embryos conceived in vitro that have not inherited the disease-associated genotype. PGD has been around since 1990, but occasionally headlines trumpet it as new.

So yes, filtering out mutations with rigorous and actionable carrier tests can ultimately alter the gene pool. And because the selection is directional, this appears to be eugenic by  permitting only certain gene variants into the next generation. But this isn’t really eugenics, because the important descriptor of eugenics is INTENT; that of medical genetic screening and testing is CHOICE. The goal of the first is sociological, the second, biological.

Genetic screening and testing often aim to avoid a medical situation in a family, not to “improve” the genetic structure of a future population. And we should never assume that all families will choose that path. I’ve talked to families that have more than one child with spinal muscular atrophy, or with a blood disorder, because preventing the birth of another affected child may seem a rejection of the beloved existing one. (See the DNA Science posts about the Amish for more examples.) Families must be allowed that choice. That’s what genetic counseling is all about.

And so I don’t think that any medical genetic screening or testing is eugenic, and I welcome the coming expansion of the opportunity to learn what’s in some of our DNA to more people.

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Black Pee Disease Offers New View of Arthritic Joints

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AlkaptonuriaA new cause of osteoarthritis identified by research on a rare disease,” ran the headline of a news release a few weeks ago. I was drawn to “rare disease,” even though I actually have osteoarthritis. When I read “alkaptonuria,” I was catapulted back more than a century to the first description of an “inborn error of metabolism.” The release announced a paper in the October Journal of Anatomy, which is behind a paywall.

So oft-told in the genetics lore is the story of understanding alkaptonuria that any geneticist would have recognized the reference instantly, as would most science writers. But the “aggregators” of science news? Not so much.

Google the headline and the parroting appears, oddly enough some of the echoes atop the original news release. One version invented a spin to up the excitement: “Scientists hoped to find out information on a rare disease. What they found instead was a potential cause of osteoarthritis,” with the subhead “An Accidental Discovery.” Please, give the researchers some credit for knowing to look at alkaptonuria as a model for osteoarthritis.

Joints commonly affected in osteoarthritis.

Joints commonly affected in osteoarthritis.

Investigating a rare disorder for insight about a common one is a classic strategy, not simply good luck. Statin drugs, for example, grew out of research on the one-in-a-million children who die young of heart attacks and strokes due to familial hypercholesterolemia (FH). Several DNA Science posts deal with a drug for the rapid-aging disease progeria that may also help those with conventional atherosclerosis.

Alkaptonuria is not quite as rare as FH, but is much more so than osteoarthritis. Alkaptonuria affects 1 in 250,000; osteoarthritis affects 13.9% of those over age 25 and 33.6% of people over age 65. lists 5 studies for alkaptonuria (all for the same drug already used for a similar condition), and more than 2,000 for osteoarthritis.

Sir Archibald Garrod

Sir Archibald Garrod

To introduce “inborn errors of metabolism” in my human genetics textbook (new edition out soon!) I tell the tale of Sir Archibald Garrod and alkaptonuria. In earlier editions I wrote that the first sign is “urine that turns black upon standing,” which unfortunately caused legions of college students to think that people with the disease should sit down when they pee. This is why we authors need editors. The urine must stand, not the urinator (see photo above).

Sir Garrod (1857-1936) was a physician at St. Bartholomew’s in London when he investigated the odd disease at the turn of the twentieth century. The initial report in The Lancet in 1902 described the telltale excretion of homogentisic acid in urine that turned black upon standing. Sir Garrod focused on the observation that when one child had black urine, a sibling sometimes did too; 19 of 32 cases were from only 7 families. Plus, parents of affected children were more often first cousins than expected for such a rare condition.

Sir Garrod termed alkaptonuria an “alternative mode of metabolism,” realizing that people vary. He entitled that 1902 paper “The incidence of alkaptonuria: a study in chemical individuality.” It is that individuality that today’s exome and genome sequencing, not to mention genome-wide association studies, seek to reveal at the DNA level.

The phrase “inborn error of metabolism” didn’t appear until Sir Garrod’s Croonian Lectures to the Royal College of Physicians, published in 1909. That paper introduced “Garrod’s tetrad” of alkaptonuria, cystinuria, pentosuria, and albinism, defining an entire class of inherited illnesses.

Timing is critical in the story. Back in 1902, Mendel’s laws had just been rediscovered. That’s why much of  classic Lancet paper addresses whether the preponderance of cousin-cousin parental pairings and familial clustering revealed the recessive inheritance that Mendel had described so elegantly for peas.

Sir Garrod was astonishingly ahead of his time, zeroing in on the “one-gene_one-enzyme” hypothesis that’s usually attributed to studies in bread mold circa 1941. The enzyme behind alkaptonuria wouldn’t be discovered until 1958, the gene in 1996. In today’s world of massive sequencing projects, I’m still stunned by the insights of long-ago researchers who deduced patterns of inheritance from what they could observe.

Homogentisic acid

Homogentisic acid

In a nutshell, an inborn error blocks synthesis of an enzyme that is part of a metabolic pathway. Like a garden hose with a kink, stuff before the block builds up, and the stuff after is a dribble, or nothing.

In alkaptonuria, the deficient enzyme is homogentisic acid 1,2-dioxygenase, and the stuff that builds up, homogentisic acid, forms the greenish-black alkapton when exposed to oxygen (when a urine stream hits the air, or a splayed diaper).

431px-StateLibQld_1_49792_Advertisement_for_Dunlop_garden_hosesTyrosine is one of the 20 amino acids of life. Five stepwise reactions break it down, ultimately providing starting materials for production of thyroid and other hormones, the pigment melanin, and entrants to the energy pathways. Block a step, and a specific inborn error results. Alkaptonuria intervenes between steps two and three; blocks at the other points cause tyrosinemia. All hamper utilization of dietary proteins.

Darkened vertebral disc in alkaptonuria

Darkened vertebral disc in alkaptonuria

Early in life, alkaptonuria is mostly a peculiarity. The pigmentation – called ochronosis – typically doesn’t affect health until after age 30, when it darkens and degrades cartilage. The tips of the ears may blacken. Treatment is painkillers and joint replacement surgery to allieve painful arthritis. But alkaptonuria also causes kidney stones, heart valve damage, tendon and muscle rupture, and fractures.

The arthritis of alkaptonuria is like that of the more common osteoarthritis, but is even more like a “novel pathology” of racehorses described by Alan Boyde, a professor of mineralized tissue biology (and a PhD and dentist) at the Barts and the London School of Medicine and Dentistry, in 2011.

Dr. Boyde and his group dissected digits of euthanized racehorses, and probed them non-invasively with “nanoindentation” and a slew of imaging techniques. They found “high density mineralized protrusions” – HDMPs. Hard spikes filling joint spaces. Ouch.

The key term is “non-invasively,” because it turns out that the reason these painful spikes haven’t been seen in those of us with run-of-the-mill osteoarthritis is that the technique to study joints destroys them! (See Heisenberg uncertainty principle: don’t alter what you’re trying to study!)

When Dr. Boyde and colleague Jim Gallagher, PhD, from the University of Liverpool’s Institute of Ageing and Chronic Disease and co-workers replaced a hip joint in a 49-year-old man with alkaptonuria, they decided to take a closer, less-destructive look. So instead of dissolving away hard stuff in the joint so they could see better, the researchers used a microtome to gently slice the tissue, like roast beef at a deli.

They saw HDMPs.

Spikes in a hip joint (University of Liverpool)

Spikes in a hip joint (University of Liverpool)

The researchers elaborate in the paper in The Journal of Anatomy that “despite extensive investigation, there is still a lack of knowledge of the microanatomical changes that ensue in osteoarthritis and their relationship to clinical symptoms. In part, this is because most histopathological studies of arthroses in humans have relied on thin sections of decalcified tissue, in which all evidence of mineral distribution in bone and calcified cartilage is destroyed.”

When the researchers went back to MRIs of the man’s hip, the telltale HDMPs were indeed there – but had gone unnoticed.

The next step was to look at joints from patients with osteoarthritis, which the investigators did for hip joints from two replacements and six cadavers. Keeping the joints intact again revealed the spikes of calcification. “We found several instances, enough to assure us that the research field should now be on the lookout for them,” the investigators write.

The spikes tend to appear near dead cells. Summed up Dr. Gallagher, “These small, sharp particles could act like an abrasive powder scouring the surfaces of the joint.”

Interestingly, the man with alkaptonuria had complained of severe joint pain, yet conventional X-rays had not shown advanced joint destruction. This reminds me of my husband’s frustrating visit to an orthopedist who informed him that he was imagining his severe back pain because the tools at the doc’s disposal hadn’t shown anything abnormal.

My own osteoarthritis appeared at age 33, as it did in my mother and her mother. Fortunately it only affects my hands, which I discovered upon whacking one of them and suffering surprisingly intense and long-lived pain, at about the same time that I became unable to play an F chord on guitar or form a fist. It’s in my neck and toes, but doesn’t really bother me much.

Random lessons learned from the alkaptonuria/osteoarthritis story:

  • Studying rare diseases in people and animal models (like racehorses) can unveil pathological mechanisms behind more-common, less-severe, counterparts.
  • If a physician claims a condition doesn’t exist, find a practitioner who will look at the problem another way.
  • In medical genetics, old stories are still valuable. It’s not all about genomics.
  • News aggregators and “content providers” who repeat repeat repeat verbatim and work for very little money are killing jobs for science writers, who have the experience to recognize the significance and backstory of news — and so much of science news these days reflects poorly-done studies (a 7-kid autism study on the nightly news?) or isn’t really news at all.
  • A frequent complaint about new editions of textbooks, such as the human anatomy and physiology textbooks I co-author, is that facts don’t change enough to warrant revision, that we know all there is to know about the human body. Not true.
  • The good news for human runners from horses is that development of joint spikes was not significantly associated with number of racing seasons, age, earnings, number of days in training, total distance galloped in one’s career, or presence of wear lines.
  • It’s ok to stand while peeing, even if you have alkaptonuria.


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Medical Success Stories: From Cystic Fibrosis to Diabetes

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dnaA skinny little boy, with mocha skin and curly black hair, lived in the apartment building next door when I was growing up in Brooklyn in the 1960s. I don’t remember his name, but I recall that he didn’t live long enough to go to kindergarten. He had cystic fibrosis.

Today’s tots with CF face a far brighter future. A recent report in the Annals of Internal Medicine applied trends in survival from 2000 to 2010 to project life expectancy for children diagnosed in 2010: 37 years for girls and 40 years for boys. (The difference may reflect hormones or the extra creatinine in the more muscular male of the species.) Factoring in the current rate of treatment improvements gives a soaring median survival of 54 years for women and 58 years for men when those kids grow up!

This is spectacular news, although some younger people with severe disease will still contribute to the lower end of the survival curve. (See my write-up in Medscape and a recent post here on the history of CF.)

Cystic fibrosis results from an absent or malformed chloride channel.

Cystic fibrosis results from an absent or malformed chloride channel.

The Cystic Fibrosis Foundation Patient Registry began in 1966, about when my young neighbor died. It has followed 26,000 of the nearly 35,000 individuals with CF in the U.S., with 5,000 added over the past decade as treatments have expanded and people with milder symptoms added.

In the early days, deaths were more often due to malnutrition than to the impaired respiration for which the disease is best known.

Success has come from diverse realms.

First came high-calorie diets, digestive enzymes mixed into applesauce, and airway clearance exercises, eventually helped with devices such as vibrating vests. Then came a parade of drugs: antibiotics, mucolytics, and more recently Kalydeco to refold misfolded CFTR (CF transmembrane conductance regulator) protein, a drug so effective that it’s Facebook page is called Kalydeco Miracles. And treatments start sooner in life thanks to universal newborn screening (since 2009) and prenatal carrier testing.

The definition of CF continues to evolve as more mutation combinations are identified and their phenotypes described. It has never made sense to me that different mutations in the CFTR gene all produce what we call cystic fibrosis, yet different mutations in the



beta globin gene cause different clinical entities. Hemoglobin C and sickle cell disease even affect the same amino acid position. The situation in naming single-gene diseases seems a little like how lumpers and splitters see biological classification.

But that may be changing. A recent report in PLOS Genetics suggests that CF is two diseases, defined by whether or not the lungs are affected. At least nine variants of CFTR spare the lungs, but cause male infertility, pancreatitis, or sinusitis — in some men, all three.

“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids. When that doesn’t happen, the acids cause the inflammation, cyst formation and scarring of severe pancreatitis. Bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function,” explains co-author David C. Whitcomb, MD, PhD and chief of gastroenterology, hepatology and nutrition at the University of Pittsburgh School of Medicine. In times past, CF wasn’t part of the differential diagnosis for men with pancreatitis, chronic sinusitis and infertility, but with working lungs.

CF affects more than the respiratory system.

CF affects more than the respiratory system.

“I know one MD who got through med school a severe asthmatic, now diagnosed with CF. We are diagnosing people better at all ages, and newborns are being screened, which contribute to increase in life expectancy,” says Paul Quinton, PhD, a professor of biomedical sciences at the University of California, Riverside, School of Medicine and medical advisor to Cystic Fibrosis Research Inc.. He has CF.



Tracking the natural history of a disease, which patient registries makes possible, is crucial in determining whether a new treatment works. For example, a recent DNA Science post asked whether boys with Duchenne muscular dystrophy who walked farther on a treadmill in a set time after receiving an experimental genetic treatment had really improved, or if their strides were within the range of normal for the disease.

Natural history studies reveal aspects of disease that could be important in developing treatments. For CF, the registry revealed a period of increased risk during adolescence. Until age 10, annual mortality is below 0.5%, but it jumps during the teen years to 3-4% before plateauing at age 25.

An editorial accompanying the Annals of Internal Medicine paper suggests suggests that the tendency of teens to not eat so well and forego treatments and therapies, and increased susceptibility to pathogens such as Pseudomonas aeruginosa and MRSA, might explain the vulnerability.

How will the health care system embrace a population of adults with CF?
While the editorialists claim “caring for adults with CF requires a village,” Lisa Tuchman MD, MPH, an adolescent medicine specialist at Children’s National Medical Center, is more positive. “We‘re seeing a trend across all pediatric-onset health conditions. For CF there has been a lot of thoughtful planning and careful analysis, mostly facilitated by the registry.” Dr. Tuchman and Michael Schwartz, MD, from the Pediatric Pulmonary Medicine & Cystic Fibrosis Center, Lehigh Valley Health Network, recently published a study in Pediatrics about successful transition to adult care for people with CF.

I asked Dr. Tuchman whether there are precedents for extended-survival patient populations. “Lots! Over 90% of little kids who get cancer are going to survive, so the system has responded by creating centers for adult survivors of childhood cancers. We see this in sickle cell disease, adult programs because people are living longer with it. And a lot of babies born with HIV disease are now young adults transferred to adult health care systems. It is across the board: metabolic diseases, hemophilia, diabetes. There’s a growing population of adults with pediatric-onset conditions,” she said.

A brute-force attack on symptoms, coupled with a targeted molecular approach, has tamed cystic fibrosis. Although news reports describe Kalydeco as correcting CF at its source, to my geneticist mind, the source of inherited disease is not the protein, but the gene that encodes it. And that’s where gene therapy comes in. It, too, has had recent spectacular successes.

Corey Haas would likely have been blind by now, if not for gene therapy.

Corey Haas would likely have been blind by now, if not for gene therapy.

One of my books chronicles development of gene therapy for Leber congenital amaurosis type 2, which has given vision to more than 200 people, many of them children. Other blinding conditions aren’t far behind.

At the American Society of Gene and Cell Therapy annual meeting last May, I heard similar stories, most notably for adenosine deaminase deficiency and severe combined immune deficiency (SCID) X1. Said Adrian Thrasher, MD, PhD, from Great Ormond Street Hospital for Children of ADA deficiency, “We expect to cure a majority of these kids today if they can have a bone marrow transplant, but if they can’t …” and he then launched into the details of ongoing clinical trials for gene therapy. It works, saving children who would otherwise die in infancy from infection. ADA deficiency, like CF, is no longer a “life-shortening inherited disease.”

And the list will grow, especially as “traditional” gene therapy of supplying working genes shares successes with genome editing techniques that actually replace or fix faulty genes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

Although I know double-blinded, controlled clinical trials are the best way to demonstrate efficacy of a new treatment, the most compelling example for me was watching my daughter Heather following her gastric bypass surgery last May.

Her type 2 diabetes vanished, in just 4 days.

I’d read the reports of gastric bypass surgery curing diabetes. And Heather’s physician had told me that more than 90% of the bypass patients with diabetes at Albany Medical Center no longer had the disease. The hypothesized mechanisms make sense: dampened secretion of ghrelin, the stomach’s hunger hormone; or forcing glucose out of the bloodstream into the rerouted small intestine to provide energy to digest food that’s a bit chunkier than normal.

Heather’s surgery had been delayed two months because she couldn’t get her A1C down – the 3-month measure of blood glucose. She went from one to two to three oral diabetes drugs, with exercise and a very low carb diet. I even invented a low glycemic index soup/stew that helped a little. But only insulin worked. Looking ahead to a lifetime of treating diabetes is what pushed Heather to have the surgery.

Someday, gastric bypass surgery could be a front-line treatment for type 2 diabetes, even among people of normal weight. In terms of both economics and quality of life, it makes sense. Or perhaps we’ll find a way to less-invasively recreate the altered microbiome of a person after weight loss surgery who no longer has diabetes.

Double Helix with StethoscopeLet’s hope that cystic fibrosis, Leber congenital amaurosis, and type 2 diabetes are only the beginning of a trend towards tackling disease, in a multitude of ways.

(Update: Eman in Liberia from my last post remains healthy, and is trying to volunteer with MSF until med school restarts. And I’m recovering from major surgery, so may miss a week of posting here and there.)

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Update: How Ebola Kills

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Eman Gokpolu (with Larry) is my African "son." He sends frequent updates from Liberia.

Eman Gokpolu (with little Larry, named for my husband) is our African “son.” He sends frequent updates from Liberia.

UPDATE OCT. 7:  Emmanuel (my “son”) and his family, in Liberia, are still all healthy! The post below is from mid-August, when much of the US still didn’t care about Ebola because it wasn’t here. It includes the immune system basics that rarely make it into media coverage.

Sunday, August 17:

Eman’s emails arrive hours ahead of the news here.

“An Ebola quarantine site was  attacked and looted. News is that most of the patients have escaped. This is going to put more fear into the population. All this because people are denying the virus.  More people might get exposed.  I’m so weak I can’t wake up this morning. Its 6:00 pm and I am still in bed listening to the news.  All this happened in a very populated area called West Point. Got pain all over my body. Keep me in your meditations.”

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. Instead, he is a “sensitizer,” educating people on how to avoid infection.

Emmanuel is a medical student in Liberia whom my husband and I have been supporting since he contacted me after reading my human genetics textbook in 2007. Until the fever hit him last weekend, he dedicated himself to “sensitization,” educating the public about how to stay safe. But now he’s too sick and weak to venture out.

His email from Monday, August 18, said only “Need help!

Eman is our son in the African sense, not based on his DNA. And our families have grown close. Some of the funds we sent to see him through medical school helped put his mother through nursing school. It costs a fraction of medical education here.

The emails and texts from Liberia are eerie in the face of the crumbling infrastructure, the abandoned hospitals and schools. Eman taps on a phone these days, too terrified to use an Internet cafe as he has in the past. We know he’s in trouble when his brother Joseph takes over — it means Eman is in the hospital. It’s happened for cholera, amoebiasis, and cerebral malaria more than once. Fighting infection is a way of life in Liberia.

I’m mortified when the news here focuses on the deaths of individuals — tragic as they may be — while the populations of African nations like Liberia, of the entire continent, are under threat. Eman wants to know why the US didn’t pay attention until the arrival here of two patients, who were treated. So do I.


The stark seeming-simplicity of the Ebola virus flashes across my mind whenever I receive an email from Eman.

Ebola virus has a mere 7 protein-encoding genes, but the RNA that is its genetic material holds hidden information. One key gene (GP, for glycoprotein) has an overlapping reading frame so that an alternate form harbors a stretch of added adenines. And the encoded protein is cut after translation, generating a mature secreted form that sits on the surfaces of viral particles, as well as a sugar-coated smaller part, like a moon carved from a planet.

(Wikimedia Commons)

(Wikimedia Commons)

The irony of it all is stunning. Genetics and genomics journals overflow with data. Always more exomes, more genomes, meta-analyses of meta-analyses that search for meaning among the nearly limitless combinations of variants of our 20,000 or so genes. And yet a 7-gene “infectious particle,” so streamlined it isn’t even a cell, isn’t even alive, can reduce a human body to a puddle, inner barriers dissolving into nothingness, within days.

How does Ebola virus, so much simpler than influenza, than HIV, do it?

Ebola virus homes to certain immune system cells as well as the boxy epithelial cells that aggregate into layers and the single bathroom-tile-like endothelial cells. Inside the body, the virus first tackles innate immunity – the immediate and generalized response to infection. Ebola commandeers monocytes and macrophages, the wandering cells that travel around the body, dividing, distributing its deadly cargo.

Meanwhile, the virus replicates like crazy.

(Wikimedia Commons)

(Wikimedia Commons)

In those who will not survive, the innate immune response goes on a tad too long. The virus also invades dendritic cells. These are the sentries that “present” the pathogen’s provoking antigens to the parts of the immune system that carry out the second phase, the slower and targeted adaptive response. And indirectly, mysteriously, lymphocytes die en masse, instead of producing antibodies.

Yet at the same time, a “cytokine storm” erupts, sending other arms of the immune response into overdrive. Levels of gamma interferon, interleukins 2 and 10, and tumor necrosis factor soar, triggering fever and flu-like symptoms. Yet it’s as if there’s no interferon at all. Viruses do not see it.

The bizarre immune response during Ebola infection is rightfully termed “paradoxical,” at once too slow, too little, too intense.

Then the body’s barriers begin to break down.

The endothelial cells that curl into the tiny tubes that are the capillaries, and also line the interiors of larger blood vessels, contort into blobs. Holes appear. Barriers melt away, and the fluids that they contained redistribute. The still-crazily-replicating virus now has direct access to organs, favoring the adrenal cortex (plunging blood pressure), the kidneys, gonads, spleen, and most dangerous, the liver.



The final stage is the bleeding, as the liver’s output of clotting factors becomes unhinged. One protein in particular goes by various names: in the older literature it’s simply “tissue factor,” but is also known as thromboplastin, CD142, and factor III.

Whatever it’s called, this cell surface glycoprotein converts prothrombin into thrombin, the essential final step in blood clotting. The fact that no deficiency of thromboplastin is known – the others cause hemophilias and other clotting disorders – belies its importance.

In Ebola infection, thromboplastin is too active, ushering in disseminated intravascular coagulation. Tiny clots form in blood vessels everywhere. Organ necrosis sets in as the blood supply ebbs, and clotting factors needed to stanch greater breaches as the blood vessels come apart become depleted. Hemorrhaging begins as the biochemical balance so critical to appropriate clotting vanishes.

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

A human body overwhelmed with Ebola virus is like a castle whose defenses fail, from the inside out, all orchestrated by that puzzling handful of genes.

GP targets the virus to certain cell types, deforms the endothelium, and destroys antigen presentation. ZMapp, the drug being given to a handful of infected people ahead of human testing because it worked in macaques, counters GP. It consists of three monoclonal antibodies produced in tobacco cells.

Gamma interferon

Gamma interferon

VP24 cuts off the host transcription factor STAT1, which is required to use gamma interferon, according to a recent report in Cell Host & Microbe. And VP40 protein, because it forms the outside of the virus, should elicit an antibody response, only it usually doesn’t.

The power of a virus such as Ebola tends to evoke anthropomorphism. But the virus isn’t intentionally trying to kill people, as one prominent researcher told the New York Times, calling the virus “a survivor. It does what it can to avoid the human immune system.” It doesn’t think.

Another type of survivor might provide the clues necessary to stop the current epidemic: people whose immune systems can fight off the virus.

Just as HIV antivirals were developed using clues from people who never became infected despite repeated exposure, a solution to Ebola hemorrhagic fever might lie among individuals who recover.

Survivors have 10 million viruses per milliliter of blood serum; people who succumb have 10 billion. So far we know that the immune response in people who survive is subtly distinctive, the innate response turning off at a specific point and the adaptive response beginning in time to help, neither becoming overactive. Identifying biomarkers may reveal the specifics that drive resistance, such as an adhesion factor that re-attaches torn endothelium.

eman gradEbola hemorrhagic fever is the consequence of runaway viral replication against a backdrop of a strangely deranged immune response. We know the viral genome sequence, and I’m sure the genome sequences of survivors are being or will soon be sequenced. I hope it is only a matter of time until researchers deduce how variations of the 20,000-gene human genome or its expression resist the 7-gene genome of Ebola virus, and figure out how to replicate the response.

Until they do, I’m petrified. I just got an email sent from Eman’s phone — from Joseph, August 20.

“Eman walked to the hospital today because according to him, he is not doing well. He called me up in pain. Luckily, its not Ebola. We were so scared. He’s admitted. No word yet. I will keep you informed. Joseph”

Update Sunday August 24: Eman is still in the hospital, but he “only” has hookworms and malaria (which he always seems to have). When he gets out tomorrow, he plans to volunteer with MSF to fight Ebola.


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ALS Target: Microglia

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deboer1HRGlia, perhaps the most underappreciated of cell types, are finally getting some attention. A new report in Science Translational Medicine from Kevin Eggan’s group at the Harvard Stem Cell Institute validates the role of microglia in amyotrophic lateral sclerosis – aka ALS, motor neuron disease or Lou Gehrig’s disease — and investigates how to manipulate them to extend life, in a mouse model for now.

Often described as inert scaffolding, bystanders, or background cells, neuroglial cells – glia for short– actually do quite a lot. In the central nervous system, the several types -– astrocytes, oligodendrocytes, ependymal cells, and microglia — provide nutrients and growth factors, mop up excess neurotransmitters from synapses, form the intricate architecture that supports axons, provide insulating myelin, and control the communications of neurons.

The relative numbers of neurons and glia have long been a matter of debate, but consensus seems to be emerging of a near 1:1 ratio. And because neurons don’t divide and glia do, there’s a lot of life and death among the so-called bystanders. Not surprisingly, when brain tumors form, they’re typically glial. Neurons must revert to a more plastic developmental state to veer onto a pathway towards cancer.

When I began coauthoring a human anatomy and physiology textbook years ago, one of the first things I did was to redo the glia section, freeing them from their stereotyped supportive roles and giving them proper respect.

All specialized cells derive from pathways that branch from stem cells. Most glia are cousins of sorts to neurons, descending from division of the same neural progenitor cells. Yet some microglia come from hematopoietic stem cells, the “mother” cells of the bone marrow. Brain cells coming from the bone marrow makes it possible to treat some brain diseases with bone marrow transplant, such as adrenoleukodystrophy. lists a few such efforts for ALS.

Microglia mediate signaling of prostanoids, which include the prostaglandins, hormone-like fatty acids that control inflammation, among other activities. In the brain microglia aggregate near damage, but in ALS, overactive versions of the cells might contribute to the pathology. PET scans show supercharged microglia in the brains of ALS patients, and heightened signaling in their spinal fluid.

Dr. Eggan and colleagues called attention to the possible role of microglia in ALS in 2008. “Now 6 years later, after considerable effort and many long-term experiments, we’ve been able to better pinpoint the source of those signals in the nervous system in an animal model, as well as show that the prediction we made using a stem cell model of disease can hold up to closer scrutiny in the context of a whole animal,” Dr. Eggan said in a news conference yesterday. The research trajectory is in a sense circuitous, demonstrating mechanisms in human cells that are then repeated in mice, to collect evidence to catalyze clinical trials of compounds that intervene in the pathological process.


Human motor neuron from iPS cells from ALS patient (Gist Croft + MacKenzie Weygandt)

Human motor neuron from iPS cells from ALS patient (Gist Croft + MacKenzie Weygandt)

Using human embryonic stem (hES) cells or induced pluripotent stem (iPS) cells is particularly important in studying diseases of the nervous system because neurons don’t divide. Otherwise where would new ones come from in a culture dish?

Contrary to the popular but deficient definition of stem cells as “cells that can turn into any cell type,” the defining characteristic is ability to self-renew – make another stem cell. If stem cells magically “turned into any cell type in the body,” there would quickly be nothing left to keep things going.

A stem cell can self-renew and generate a neural progenitor cell that in turn can divide to give rise to neurons and glia. The Eggan team first created iPS cells from an ALS patient  in 2008.

Microglia apparently harm motor neurons via a specific type of overactive prostanoid receptor. First author and grad student Sophie De Boer and her colleagues at HSCI, Massachusetts General Hospital, and Boston Children’s Hospital, conducted a brilliant series of experiments that show that blocking or removing the errant receptors may be one route to extending survival in ALS.


Human embryonic stem cells

Human embryonic stem cells

In the new study, the investigators exposed human motor neurons derived from ES cells and marked with green fluorescent protein (GFP) to sheets of “toxic” glia from mice that have a form of ALS due to mutation in the superoxide dismutase 1 (SOD1) gene. At last count, 7 human genes had been implicated in the 5 to 10% of cases that are inherited; SOD1 was the first and is the best studied.

The SOD1 toxic microglia killed more than half of the neurons, but chemically blocking the receptors enabled the neurons to survive.

In complementary experiments, activating receptors in normal glia turned them toxic – but only to motor neurons, and not other neuron types. Removing the gene encoding the protein that forms the receptor had the same effect as blocking it chemically. And perhaps most important in a translational medicine sense, a short blast of antagonist had a long-lasting effect on the health of the motor neurons. Plus the effect is seen in actual living animals, increasing lifespan in mice.

The most exciting part of the new work is that it zeroes in on a “druggable” target – the DP1 receptor and its associated signalling pathways. The receptor is a G protein, a membrane-spanning molecule that is already the basis of many drugs. Said Dr. Eggan, “At least two major pharmaceutical companies have significant development programs around this receptor for another indication — niacin induced flushing.” Perhaps these candidate drugs can be retasked to inhibit inflammatory effects in ALS, he added, and possibly teamed with a seizure medication the researchers identified earlier this year that fights ALS by a different route.

640px-2006_Pro_Bowl_tackleALS is like Alzheimer and Parkinson diseases in that a shared phenotype might represent any number of different gene-environment interactions. What’s true for an individual with SOD1 ALS may not be so for a person with a different mutant gene.

The ALS patient I posted about in April, Glenn, didn’t have any known mutations, but he did have a few environmental risk factors. He played football for many years, maybe getting clunked in the head one too many times, and may have been exposed to pesticides when his boyhood home (to which he moved back as an adult) bordered fields of crops. Smoking, aspartame, and exposure to formaldehyde and heavy metals are other suspects. Reports that vitamin E protects against ALS haven’t held up.

BMAA, an amino acid implicated in ALS that is not part of dietary protein.

BMAA, an amino acid implicated in ALS that is not part of dietary protein.

Perhaps the most fascinating causal candidate is exposure to cyanobacteria (aka blue-green algae) living in cycad trees on Guam. The cyanobacteria release an amino acid called BMAA into the soil, where it makes its way through the roots to the seeds of the cycads. After biomagnification through food webs, BMAA causes an ALS-like disease when it binds proteins in the brains of some individuals, who may be genetically-predisposed to the motor neuron damage.


Do people survive ALS? The disease may be so heterogeneous that this might be possible. One commentator on my previous ALS post took me to task for not mentioning this idea, which I admit I was not aware of, but I found his tone disturbing. He wrote:

“C’mon, time to wake up and smell the coffee. People have been solving ALS for years, and the only way to really do it is change diet, psychology and lifestyle.”

He linked to a website offering accounts of recoveries, and then commented on Dr. Eggan’s team’s identification of the seizure drug for possible repurposing:

“While maybe that drug will be of some use somehow, don’t let that distract you from the overall reality of the situation. Stem cells? Eh, just learn to heal.”

There's more to finding a treatment for ALS than just "making it so."

There’s more to finding a treatment for ALS than just “making it so.”

I don’t think the commentator intended to upset ALS patients who haven’t managed to heal themselves, and I understand the value of hope. But an anti-science stance certainly isn’t going to help. I’m reminded of Captain Picard on Star Trek: Next Generation saying “make it so,” or the professor in The Music Man teaching kids to play instruments using the “think” system rather than learning music theory.

Positive thoughts aren’t enough.

Using stem cells to recapitulate the precise choreography of a disease, illuminating the various drug targets and their interactions, and then deploying drugs old and new based on those discoveries, may indeed “make it so,” slowing, vanquishing, and ultimately preventing this heartbreaking and complex disease.

I think that use of stem cells to create “diseases-in-a-dish” will turn out to be their most successful application. The very quality of self-renewal that many news reports omit is what scares me. Stem cells used therapeutically that self-renew, perhaps in places unexpected, could form a tumor.

Coincidentally, I just received an e-mail from Maurie Hill, whose participation in a clinical trial to treat Stargardt disease, a form of visual loss, was the subject of the very first DNA Science post, Human Embryonic Stem Cells Finally Reach Clinical Trials: Maurie’s Story, nearly two years ago. Alas, her vision has not improved at all, although I do not know the findings of the frequent tests she undergoes — just that she’s very disappointed.

But use of stem cells wedded to drug discovery? That’s a can’t-miss! Congrats Eggan lab for the continuing fine work.



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Gene Test Predicts Blindness After LASIK

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Granular_corneal_dystrophy_type_I._Numerous_irregular_shaped_discrete_crumb-like_corneal_opacitiesMillions of people have put aside their eyeglasses or contact lenses thanks to a procedure called LASIK. But for carriers of a rare condition called granular corneal dystrophy (GCD), LASIK can damage the cornea, even causing blindness. The Avellino DNA Dual Test for LASIK Safety, from Avellino Laboratory, can identify individuals genetically predisposed to this complication, offering a great example of an “actionable” genetic test.

Ophthalmologists can provide the cheek swab test to patients considering LASIK, and results are available within 2 days. Company founder and CEO Gene Lee pursued development of the test after learning about the genetic connection in early 2008. It’s now standard-of-care in Korea and Japan, and became available in the US in April. Insurance typically doesn’t cover it (yet), but the test is often incorporated into a work-up for LASIK, and out-of-pocket costs about $100.

“We started doing it last year and we’ve found it to give increased peace of mind and confidence in the procedure. If someone has this condition and it is clinically apparent and visible, the test would just confirm the visual findings. But a number of patients have subclinical findings or none, and this genetic test is the only way to identify the condition,” Richard Rothman, MD, an ophthalmologist who practices in Las Vegas told me. And patients who have the mutation can tell their relatives to be tested before choosing LASIK.




GCD results from mutations in the transforming growth factor beta induced (TGFΒI) gene, which encodes the protein keratoepithelin. The affected part of the cornea, the stroma, consists of extracellular matrix (the goo between cells) and stacks of collagen fibrils, with some other proteins such as fibronectin and integrins, and scant keratocytes that produce the keratoepithelin that keeps the cornea clear. Combine carrying a mutation with stress – such as radiation, hypoxia, chemotherapy, peroxide, or perhaps a laser procedure — and keratoepithelin misfolds into a gunky, amyloid-like mess.

The two types of GCD are due to mutations in different parts of the gene. The type 1 or classic presentation results from a mutation in exon 12, giving a “bread crumb” like appearance to the cornea. Type 2 is known as “Avellino” because the first identified cases, in 1988, lived in the town by that name in Italy. This type resembles a “snowflake icicle” due to a mutation in exon 4 (the exons are the parts of genes that encode protein). Other studies identified patients in Japan and Korea, and then pretty much everywhere.

For individuals who have two mutations (homozygotes), proteins deposit in the corneas during infancy, causing blindness by the teens. The condition is much milder, with later onset, in people with one mutation (heterozygotes). But if vision isn’t very impaired, or begins late in life, then visual loss rather than improvement months to years after LASIK comes as quite a shock. People can carry the mutation and not know it. And that’s where the test comes in.




LASIK (laser-assisted in situ keratomileusis) creates a thin flap in the cornea that is hinged back to reveal the middle layer, where an excimer laser is applied to alter the topography to better focus light rays on the retina. Normally, the intervention activates transforming growth factor beta to repair the wound. But in people with one mutation, the surgery makes keratoepithelin misfold and aggregate at the flap. This action accelerates the corneal dystrophy and may cause another complication in which torn collagen fibers bind various proteins, producing a “sands of Sahara” effect. Ouch.

Avellino DNA Dual TestGCD is rare. Avellino Laboratory has identified 390 people with one or two mutations among 420,000 being worked up for possible LASIK. More than 30 mutations are known, and they also account for the related condition lattice corneal dystrophy. The nomenclature is still traditionally clinical, based on appearance, but subtyping now reflects genetic distinctions. For families aware of the pattern of inheritance because homozygotes are blind, full gene sequencing is available from several labs.

Every morning, I look through digests of news releases about genetic research from a wonderful service from the American Association for the Advancement of Science called EurekAlert. A few weeks ago, the news release about the LASIK genetic test caught my eye because of its simplicity, its utility, and the fact that it looks for mutations in ONE gene. That’s unusual these days.

(Dept. of Energy)

(Dept. of Energy)

More often, the studies in the news release roster, and therefore those that make the news, deal with big data. They track thousands upon thousands of sites in genomes that vary among individuals, boiling down to a dozen or so that can serve as usually weak risk factors (genome-wide association studies or GWAS); follow epigenetics (sites of methylation) and changes in gene expression; or sequence exomes and genomes. All good of course, but usually not immediately of any help to patients. And many news releases mix up the techniques or write so vaguely that it’s difficult to know what exactly the findings are without reading the technical papers.

Around the time of the LASIK news release was another on a GWAS finding a dozen risk sites for Parkinson’s disease, a report in the Journal of Urology tracking methylation profiles of three genes that predict which prostate cancer biopsies are false negatives, and reports on finding common gene variants behind autism and schizophrenia. Inheriting a mix of variants can set the stage for each condition. An additional, triggering mutation or exposure to an environmental factor might then turn risk into reality.

These are all quite different genetic scenarios than a single gene mutation that makes itself known after surgery injures the eye.

I realize that large-scale investigations take massive and talented teamwork, and that the projects are vital to understanding pathology, which fuels new treatments. But I’m starting to feel an information overload that makes me appreciate the single-gene tests that a patient can benefit from right now. Many have been available for years, but we don’t hear about them as often as the megadata. They’re not news.

Blausen_0290_DeepVeinThrombosisPerhaps the best example of a an actionable single-gene test is the one for factor V Leiden, a mutation in a clotting factor gene. Knowing it’s there means you can avoid dangerous clots by taking blood thinners, wearing special support socks, and avoiding long plane rides or crouching for long periods, as reporter David Bloom did in 2003 when reporting from Iraq in a tank with his legs folded underneath him for hours. He died of a pulmonary embolism following deep vein thrombosis.

I hope that single-gene test panels, such as those for cardiovascular disease or Jewish genetic diseases, don’t become completely buried by the avalanche of genomic megadata.

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