Why Do Healthy People Have Harmful Mutations?

ATCG's Image with Group of People“NIH researchers pilot predictive medicine by studying healthy people’s DNA,” read the headline of a news release yesterday.

The news release, about intriguing new findings from the ClinSeq program at the National Human Genome Research Institute, states that researchers “sequenced the genomes” of 951 “healthy participants.” 103 of the people had disease-associated mutations, and of 79 of them followed up clinically, 34 indeed had the diseases their genotypes predicted, but apparently hadn’t known it. More intriguing were the 43 participants who had disease-causing genotypes, but were healthy.

That’s certainly news, but it doesn’t quite echo the paper it describes, published in The American Journal of Human Genetics.

The participants were 45 to 65 years of age at enrollment and were selected for a range of atherosclerosis phenotypes,” the paper states. The researchers factored in the abnormal lipid profiles. The paper also clearly states that exomes (the 2% or so of the genome that encodes protein) were considered, not full genomes, and scanned for known, dominant mutations that cause “loss-of-function.” And the focus on adults eliminates the many single-gene disorders that start in childhood.

So the study isn’t quite the grab-bag of average Jills and Joes that the news release suggests. But the results are compelling, and important to the precision medicine effort. They provide powerful evidence for concepts from classical genetics.

Chapter 5 in all eleven editions of my human genetics textbook, “Beyond Mendel’s Laws,” addresses the complexities behind the effects of mutations.

To start, 3 words describe single genes:

Polydactyly_sreeakhilPenetrance. A person who has a genotype but not the corresponding phenotype (trait or illness) is “non-penetrant,” and the gene “incompletely penetrant.” A mom with 10 fingers and 10 toes whose child and parent have extra fingers and toes (polydactyly) is non-penetrant. The mom would have to have the mutation to pass it to her child.

Expressivity. People vary in their experience of the same disease. A child with sickle cell disease may require frequent hospitalization, while his sibling, who has the disease too, does not.

Pleiotropy. Single-gene diseases may have many symptoms, and different people have different subsets of them. Or, a person may have a symptom not known to be part of a disease, but it really is. This “atypical presentation” is the case for Nicholas Volker, one of the first patients with an undiagnosed disease to get an answer through exome sequencing. The boy’s dissolving intestines were due to XIAP deficiency, an immune disorder not previously known to have this symptom.

When considering more than one gene, two more terms come into play:

Genetic heterogeneity. Mutations in more than one gene can cause the same phenotype. Famous case: parents were found guilty of child abuse because their kids had broken bones and the parents didn’t have mutations in the one gene then known to cause osteogenesis imperfecta. They had mutations in a different gene that also breaks bones – several are now known.
Alzheimer Disease

Epistasis. One gene affects another. Spinal muscular atrophy (SMA1) is like severe, rapid ALS in a child. The abnormal protein shortens axons, hastening motor neuron death. In one family, one child died very young, but another lived several years longer. The more fortunate sibling had a variant in a different gene, plastin 3, which extends axons.

Similarly, siblings who both inherit Huntington’s disease (last week’s post) may get sick at different ages based on the rate of division of stem cells in the brain, the luckier individual making up for the cell death of HD faster than the other. In fact, if the course slows enough, the person may die of something else and never know she or he had HD, unless there was a genetic test. That looks like a healthy person with a devastating mutation. A similar scenario is true for Alzheimer disease. Mutations in apoE4 increase risk, while mutations in the amyloid precursor protein gene lower the risk.

SMA1, HD, and Alzheimer disease are devastating brain diseases. The idea that a person could have a single-gene test that finds a mutation, but the associated disease could be tempered by a variant of a different gene that isn’t tested for, scares me.



Another explanation for how a healthy person can have a genetic disease is that people, and sometimes their physicians, aren’t thinking about genetics, especially when a symptom is common. Leslie Biesecker, corresponding author of the new paper, offers an example: “A couple of the participants with LDLR (low density lipoprotein receptor) mutations thought they just had garden variety high cholesterol, when in fact they had familial hypercholesterolemia.”

The study also found people with heart defects, immune deficiencies, blood disorders, blistering feet, or stubby fingers who had no idea that they or their family members had an inherited disease. Further investigation found biochemical evidence, symptoms, or telling characteristics.

One family with lipodystrophy due to mutation in the PPARG gene thought they all just had prominent musculature which was unrelated to their diabetes or abnormal lipid profiles. Another had hair follicle tumors caused by a mutation in the FLCN gene. That was important to know because it elevates risk of kidney cancer. And speaking of cancer, 19 of the participants had cancer susceptibility mutations well known for their incomplete penetrance, such as the BRCA genes. Only 6 of the 19 had family histories of the associated cancers.

I can think of lots of other examples of unrecognized genetic disease:

Chronic sinusitis may be cystic fibrosis.

• Bleeding easily and for a long time may signal a clotting factor deficiency, and the study indeed found 5 cases.

• Highly bendable body parts may be due to Ehlers-Danlos syndrome.



• A person with a few café-au-lait spots may have neurofibromatosis.

• I don’t sweat much, and neither did my mother nor her mother. I’ve wondered if I have hypohidrotic ectodermal dysplasia, but only the one symptom.

Sometimes, the genetic evidence is just a mystery. In the study, for example, four people should have had glaucoma and two should have cataracts, according to their genes — but didn’t.

Practically speaking, people who don’t receive regular health care, or if they do see a health care provider for 5 minutes, would not have an opportunity to assemble these and more subtle clinical puzzle pieces. And that’s the value of the study — exome sequencing can clearly change some peoples’ risks of a particular condition from one in thousands to about one in two, depending upon the detected mutation and its penetrance.

Earlier exome and genome sequencing experiences predicted that we’d find disease-causing genotypes among healthy people. Consider “incidental findings” (aka secondary or unsolicited) – when a medical work-up looks for one thing and finds another. Three early cases from exome screens for adults with atherosclerosis or children with developmental delay come to mind:

• A family whose members thought they had writer’s cramp actually had a neurological disease, myoclonus dystonia.

• A child had undetected Marfan syndrome. His aorta was at risk of bursting without treatment.

• A man who had been deaf from birth never realized it – he thought all people read lips.

Trolling exomes or genomes for mutations is a little like finding humor in a Stephen King horror novel. Look for one thing, find another. It happens, more often than we thought.



The new findings change the estimate of 0.02% of the US population having a genetic condition to as high as 3%, about the size of the population of New Jersey, the researchers point out. Now we need to find out why and how some genotypes cause symptoms in one individual but not in another.

To do that, we must leap beyond sequencing, to decipher all the ways that all the genes and their many variants can interact. Gene-gene interactions may explain why the boy with sickle cell disease is hospitalized often, in excruciating pain, while his sister who also has the disease has a much easier life: they’ve inherited different combinations of variants of other genes that impact the functioning of the mutant beta globin gene that they share.

Unraveling gene interactions can even reveal new drug targets. For example, the study found two men who had mutations known to cause Duchenne muscular dystrophy — but they didn’t have the disease, which surely would have been obvious in boyhood. What second gene, or circumstance or environmental factor, protects them?

Figuring out all the interactions that underlie gene expression is a challenge that dwarfs that of sequencing the first human genome, and the effort is underway. Now that’s precision medicine.

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Can We Cure Huntington’s Disease?

INSIDE THE O'BRIENS Final CoverI didn’t cry until page 123 of Lisa Genova’s terrific new novel Inside the O’Briens. That’s when 44-year-old Boston police officer Joe O’Brien tells his four young adult offspring that his “weird temper”; his frequent toe-tapping, shoulder-shifting, and eyebrow lifting; and his inability to sequence the events in a routine crime report, are all due to Huntington’s disease (HD).

As a boy, Joe believed the neighborhood talk that his institutionalized mother was an alcoholic. He remembers his skeletal, writhing, grimacing and grunting mother as a monster, not as someone suffering from a neurological disease only trying to say “I love you” to her terrified son.

But it is a passage on page 186 that inspired this post: a genetic counselor tries to positively spin the worst-case scenario to Joe’s 21-year-old daughter Katie, who is agonizing over whether to learn her 50:50 genetic fate. If she has inherited the mutation, she likely would have at least 15 to 20 years before symptoms begin. For a similar but true story of a young woman facing genetic testing for HD, see “The Lion’s Mouth Opens” premiering on HBO June 1 at 9 PM.

A lot of things can change in that amount of time. There’s plenty of real hope in the research being done. We could have a really effective treatment or cure by then,” the counselor says.

I’ve said similar things to patients who have a genetic disease in the family. But a treatment or cure may be asking a lot — slowing or amelioration of symptoms might be what’s actually possible. I inwardly cringe at highly-publicized efforts to “find a cure” by throwing money at a medical problem – from Richard Nixon’s War on Cancer to today’s Stand Up 2 Cancer — as if the answer has been hiding and we just haven’t seen it. Those campaigns make me think of HD. Sometimes money isn’t enough.


The privately-funded CHDI Foundation has been donating $100 million annually to HD research for years, “to develop drugs that will slow the progression of Huntington’s disease and provide meaningful clinical benefit to patients as quickly as possible.” (Disclosure: I’ve written research reports for CHDI.) Like treatments for HIV infection and cancer, slowing disease progression and easing day-to-day life are valid goals, and may be enough to change a terminal illness into a chronic disease.

With those caveats, HD research may finally be turning a corner from preclinical studies to clinical trials. From 1999 through 2002, there were only four trials for HD, but from 2011 to 2014, 28. More than 1,500 people who have HD are now participating in clinical trials, as well as many of their still-healthy relatives who are “pre-manifest,” having inherited a mutation but not yet showing measurable signs or symptoms.


Karli Mukka and her dad Karl Mervar died within weeks of each other. Karli had the juvenile form of HD. (credit: Jane Mervar)

Kudos to Dr. Genova for mentioning juvenile HD. Karli and Karl died within weeks of each other.  (credit: Jane Mervar)

Exactly two years ago, DNA Science introduced a family that illustrates an extreme of the multi-generational manifestation of HD, Juvenile Huntington’s Disease: The Cruel Mutation. Karli and her father Karl died within 6 weeks of each other, and in this more recent post, Karli’s sister Jacey discussed the juvenile form of the disease, which she has too.

Lisa Genova vividly conveys the rarity of HD with her own metric: the number of people with HD about equals the number of Red Sox fans who fit into Fenway Park in a scene in the book – about 37,000. The number who are “at-risk” – who have a parent with HD – is about five times that.

Each child of a person with HD has a 50% chance of having inherited the condition. If that happens, then the chance of developing symptoms is 100%, if a person lives long enough. Such “complete penetrance” is very rare. Symptoms typically begin in one’s thirties, but changes in cognition (like the sudden inability to follow a favorite recipe) and mood (irrational anger) may creep in a decade or more earlier.

HD is an “expanding repeat” disorder. The gene (HTT) that encodes a protein called  huntingtin (Htt) includes at its start a repeat of three DNA bases that encodes the RNA triplet CAG, which specifies the amino acid glutamine. Thirty-five or fewer “CAG repeats” is normal, but anything greater than 40 spells HD, with 36-39 copies a gray zone. Too many CAGs result in huntingtin protein that clogs brain parts that control movement and aspects of cognition.

Genova illuminates the meaning of extra repeats with a gut-wrenching scene in which Katie takes a black Sharpie and scribbles strings of 47 CAGs all over her bedroom wall. Her sister Meghan, a professional dancer, has just gotten the results of the genetic test that she took following required genetic counseling. Katie, sobbing, scrawls “the number of CAG repeats dancing inside the mind of her only sister.”

Woody Guthrie put a face on HD.

Woody Guthrie put a face on HD.


The fact that HD is so unlike other conditions may explain why millions of research dollars haven’t had much impact – yet. Three key distinctions are:

1. Researchers can’t compare the genomes and environmental exposures of people with the mutation who get the disease to people with the mutation who don’t get the disease. They all get it.

2. HD isn’t due to a missing enzyme that can be replaced (like inborn errors of metabolism), a misfolded protein that can be re-folded (like cystic fibrosis), or a protein factor that can be supplied (like hemophilia). HD even differs from other triplet repeat disorders, such as fragile X syndrome, in which mangled proteins don’t function. Instead, Htt has a new, “toxic gain of function.”

3. Having a working copy of the HTT gene doesn’t compensate for or hide its evil twin on the other chromosome 4. That’s why people with two HD mutations are no worse off than people with one, and why deleting the HTT gene has no effect.

These peculiarities suggest which therapeutic strategies are most likely to work.


Gene therapy for HD doesn’t make much sense. How would adding a functional HTT gene help, when it’s already there? Blocking access to the extra genetic material seems the most logical approach to me, like redacting a phrase in a legal document with a heavy black mark, a biochemical version of Katie’s sharpie.

Perhaps the most “druggable” part of the pathology isn’t the gene or the protein, but the go-between RNA. A molecule of RNA riddled with extra-long repeats can contort in ways that can impart a hidden, second language, a powerful genomic subtext.

Repeats are scattered throughout our genomes, but extra-long ones can cause the messenger RNAs that seem to peel off of a gene to form secondary structures where G binds C within the molecule. This self-glomming can generate “R loops” where the RNA displaces one side of the DNA double helix, and ladder-like “RNA hairpins.” A hairpin motif can trigger an immune response called PKR (protein kinase RNA-activated), which is usually deployed against viruses. The errant attack unleashes inflammation in the brain, while killing neurons.

Htt aggregates (Credit: Nadine Strempel and Erich Wanker)

Htt aggregates (Credit: Nadine Strempel and Erich Wanker)

The fact that HD has no roster of drugs to choose from, as do cancer, HIV, diabetes, heart disease, and hepatitis C, certainly isn’t due to lack of effort. Here are a few recent highlights that reveal efforts to think beyond the responsible gene. (For greater detail see the excellent Cure HD blog, by the pseudononymous Gene Veritas, who is at-risk).

AGE OF ONSET     A single nucleotide polymorphism (SNP) in the promoter of the HTT gene tracks with delayed onset if it is part of  the mutant gene, yet an earlier onset if it is in the wild type (non-mutant) version. Kristina Becanovi, PhD, from the Karolinska Institute reported the findings recently in Nature Neuroscience. Although the study followed extreme cases, the discovery opens up “a smorgasbord of ideas for new therapies,” according to co-author Ola Hermanson, PhD.

Genes other than HTT affect age of onset too. Jong-Min Lee, PhD, of Massachusetts General Hospital and co-workers discovered a gene on chromosome 15 that alters age of onset by up to six years, depending upon which variant a person has inherited.

HUNTINGTIN PROTEIN     Imaging can’t capture Htt buildup well, but probing the protein’s presence in cerebrospinal fluid (CSF) may provide a window to disease progression. Ed Wild, PhD, at University College London found that the closer pre-manifest patients got to symptom onset, the higher the level of Htt in their CSF. And the worse the symptoms, the more Htt.

GENE SILENCING.     At least 14 companies are exploring variations on the gene silencing theme. ISIS Pharmaceuticals is about to launch a phase 1 clinical trial of an antisense oligonucleotide-based drug introduced into the spinal cord. Will CRISPR-Cas 9 one day replace the expanded HTT variant with one bearing a healthy 35 or fewer repeats?

STEM CELLS     An observational study called PRE-CELL is underway at the University of California at Davis’ HDSA Center of Excellence (Vicki Wheelock, MD) and Institute for Regenerative Cures (Jan Nolta, PhD) to track biomarkers, symptoms, and imaging findings as HD progresses from diagnosis. After a year, patients can  enroll in a phase 1 clinical trial that will deliver mesenchymal stem cells into the brain’s striatum. The cells are altered to overproduce brain-derived neurotrophic factor (BDNF), which may save affected neurons.

PROTEINS THAT INTERACT WITH HTT     Erich Wanker, PhD, from the Max Delbrück Center for Molecular Medicine and colleagues report in the May Genome Research a computational approach that deciphers Htt’s interactions. The tool compares expression profiles of brain-specific genes in patients who have symptoms to those of individuals who are pre-manifest. Of 13 identified “interactors,” 7 are already drug targets. Among the other six one protein, CRMP1, is expressed only in the brain. In animal models excess CRMP1 decreases Htt aggregation and cell death, and too little is associated with increased aggregation and cell toxicity. In cells, CRMP1 slows Htt aggregation.

NEW DRUGS     The only FDA-approved drug to specifically manage HD’s motor symptoms is tetrabenazine, which has adverse effects of suicidality and depression. Auspex Pharmaceuticals is testing a drug called SD809 that tackles the chorea (uncontrollable movements) without tetrabenazine’s adverse effects.

PKR inhibitors are compounds that derail the immune response to RNA hairpins.

Another drug candidate, SEN0014196, is an inhibitor of a sirtuin, which is a protein type  associated with aging. The drug, a protein deacetylase, alters transcription of HTT. In animal models it extends survival and dampens movements, and speeds clearance of Htt aggregates while not affecting normal Htt protein. But I found the Internet trail to vanish after 2012. SEN0014196, aka EX-527, is commonly used in epigenetics research, so if someone can update use in HD, please do.

There have been pharmaceutical disappointments. Clinical trials for coenzyme Q10 and creatine were halted due to lack of efficacy. But sometimes a seeming failure isn’t due to an ineffective drug, but to inadequate study design. That may be the case for pridopidine, a drug deemed ineffective in a clinical trial that considered only a subset of motor manifestations. Teva Pharmaceuticals is giving it another chance by testing total motor ability, cognition, mood, and quality of life. Teva is also evaluating a drug called laquinimod that quells brain inflammation.


Lisa Genova has accomplished the seemingly impossible in Inside the O’Briens. She’s made the story of a family shattered by HD into something approaching positive. At the risk of a spoiler, I’ll just say that the book reaches a pivotal point where the trajectory and tone change in a magical way, a way that can really help families.

I thought I knew a lot about HD, from my writing but also from spending four months as a hospice volunteer with a young man so sick that his body became unable to move at all, out of energy. Ray’s story inspired my novel about stem cells, music, and HD. But Lisa Genova, a neuroscientist, has taught me so much more.


Genetic counseling is critical in HD testing (NHGRI)

Inside the O’Briens” tells not about how to die from HD, but how to live with it in a way that guides younger generations, while enabling elders to finally understand what was wrong with their parents and grandparents, their aunts and uncles. Some readers may quibble with the ending. I did at first. But then I realized that it is a perfect metaphor for living with this genetically unusual and personally devastating inherited illness.

May is Huntington’s Disease Awareness Month. Please donate to the Huntington’s Disease Society of America or to family-run organizations, such as the Juvenile Huntington’s Disease Initiative. Although the families would love a cure, their organizations often focus on ways to make life easier, one day at a time.

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DNA Profiling of Cat Waste

Crowing_pains-PD_Looney_Tunes-_Sylvester_the_CatBring in a stool sample,” says the vet. But that’s not so easy in a multi-cat household.

I recently faced this problem when I adopted our fourth cat, Panda. Researching the issue, I found only one website that addresses the sampling of poop from a particular feline. The suggestions:
• Keep the cats in separate rooms, with separate litter boxes
• Judge consistency visually if the symptom is diarrhea
• Feed the healthy cats corn. It will mark their poop.

Because these ideas weren’t very helpful, I envisioned an at-home diagnostic kit for kittystool. It would use a set of short tandem DNA repeats, just like the CODIS system that the FBI uses. The vet or microchip company would have a DNA profile on file to which the suspect’s DNA would be compared. (This DNA Science post explains how STR DNA profiling works.)

Juice had diabetes, but it was hard to tell which cat was turning the litter to cement with telltale copious urine.

Juice had diabetes, but it was hard to tell which cat was turning the litter to cement with telltale copious urine.

Uses of my cat DNA test transcend bowel movements. For example, we lost our beloved Juicebear a year ago to diabetes, but he’d started peeing like crazy in January. For months, unable to rush to the litter box as soon as we heard the blast of urine, we’d erroneously assumed it was coming from Jelly, our eldest.

cat barfingVomit is testable too. This time of year for those of us who live outside cities, mornings often begin with the unmistakable sound of a cat retching. What comes out, at least among my crew, includes grass and rodent innards, seeds, and sometimes avian remains.

But unless one catches a feline in the act, like I did last week when Artie bit off the head of a mole in front of company, it’s difficult to discern which cat is ingesting something potentially dangerous. However, cats are supposed to be hunters. Vomiting is generally a transient event rather than a sign of a systemic or metabolic disorder, which might be reflected in bowel and urine changes. Because of that, I’d call my product CATUS (Cat Turd and Urine Sample).

cats eatingI searched the Patent and Trademark website for “DNA profiling AND feline” and got 78 hits, most immune-related diagnostics for humans, but nothing resembling DNA profiling, or even its old name, DNA fingerprinting. Why not? After all, Felis catus genomes have been sequenced, notably an Abyssinian named Cinnamon, a Russian named Boris of mixed lineage, and a wildcat named Sylvester.

Scoop_your_poopAfter the Patent and Trademark website turned up nothing, I simply googled “DNA and cat shit.” I immediately found PooPrints and similar products for city dwellers concerned about the origins of unpicked-up dog poop. Then I found a test for feline breed and heritage. I don’t think the “ancestry certificate with your cat’s geographic origin, breed information, coat genotype and sex” for $120 is quite worth it. My four felines are male, black and white, and came from shelters.

CATUS has a forensic focus, strictly identity. I’m not interested in validating a bloodline or tracking where cats crap. So I was hoping that a new endeavor called the “99 Lives” project from the University of Missouri, under the auspices of the wonderfully named Leslie Lyons, might take me up on my idea.

The 99 Lives project will sequence the genomes of 99 (or more) cats, including the domestic variety as well as “bobcats, palace cats and even tigers,” said Dr. Lyons, the Gilbreath-McLorn Endowed Professor of Comparative Medicine in the University of Missouri College of Veterinary Medicine, in a news release.

Trouser has unexplained liver disease and diabetes.

Trouser has unexplained liver disease and diabetes.

“Many cats suffer from obesity, diabetes, asthma, urinary tract infections, cancers, heart disease and infectious diseases, just like humans. The responsible DNA variations for any individual birth defect or inherited condition that affects health later in life can now be identified in any individual cat,” Dr. Lyons said.

Tens of thousands of humans and hundreds of dogs have had their genomes sequenced, but only a few cats. “The more cats we can genetically sequence, the better we will understand what causes many genetic disorders and possibly even how to prevent those problems.”

The 99 Lives project needs donations of dollars and DNA; sequencing the genome of one feline costs $7,000. I hope their results help to explain cases like my grandcat Trouser, who has feline hepatitis that led to diabetes. And I hope someone will bring personalized medicine (aka genetic analysis, it isn’t really a new idea) to the excretions and secretions that spew from our cats. If anyone knows of such a product, please comment!

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Gene Therapy for Blindness Works!

Corey Haas would likely have been blind by now, if not for gene therapy in 2008.

Corey Haas would likely have been blind by now, if not for gene therapy in 2008.

The news this week presented at a major vision conference and published in The New England Journal of Medicine about gene therapy to treat childhood blindness paints an unnecessarily grim picture. Because I wrote a book about it and know affected families, I’d like to add some much-needed perspective.

Two papers in the NEJM, Jacobson et al and Bainbridge et al, report follow-up results on gene therapy performed since 2008 for RPE65-associated Leber congenital amaurosis (RPE65-LCA for short). Various measurements and images show a continual degeneration of the photoreceptors (rods and cones) despite the fact that many patients became able to see for the first time and some still do. One of the research groups reported initial findings of continued disease in 2013, which DNA Science covered (Another bump in the road to gene therapy). This week, that bump appears to be a boulder.

The bottom line from someone (me) who’s seen kids with newfound vision: Numbers and scans don’t tell the whole story. These aren’t the only ways to assess visual function. A formerly blind child who can now ride a bike, step off a curb unaided, or see a sibling’s face should count too, even if the ability wanes.

Briard sheepdogs have a natural form of RPE65-LCA, but the new studies show it is more severe in humans. (Foundation for Retinal Research)

Briard sheepdogs have a natural form of RPE65-LCA, but the new studies show it is more severe in humans. (Foundation for Retinal Research)

Tracking continuing disease despite clinical improvement is important in making a treatment the best it can be, experts agree. But let’s not dismiss what’s been accomplished.

I spoke with Jean Bennett, MD, PhD, who leads the gene therapy trial for RPE65-LCA at Children’s Hospital of Philadelphia (CHOP), where results do not indicate continued degeneration (see my news report in Medscape). The CHOP group didn’t publish in this week’s NEJM. I also talked to Eric Pierce, MD, PhD, who worked with Dr. Bennett on the early clinical trial and is now at the Massachusetts Eye and Ear Infirmary. They point out where caveats and explanations of study design might help in interpreting the new NEJM findings.

• The number of patients followed in the two new reports is very small (3 of 15 in one study, 12 in the other) and only a tiny portion of the retinas were examined. Hundreds of patients have had the procedure. “I could pick 3 patients in our trial and look at the data and say it doesn’t work, and I can also pick another 3 and say it works fantastically,” Dr. Bennett said.

• The Jacobson paper compares treated eyes to historical samples, not to the patients’ untreated eyes, which would control for individual differences in the rate of degradation as the disease progresses and for normal aging, a more personalized approach.

• Retinal sensitivity at 6 years is still considerably higher than it was before treatment. The intervention works.

• Many patients see when they didn’t before gene therapy, even if tests such as electroretinography and optical coherence tomography (OCT) reveal impaired photoreceptor function and degeneration.

• Bainbridge et al used a promoter (a DNA sequence that controls the rate of gene expression) that wasn’t as powerful as the CHOP one, necessitating higher doses that may have caused the inflammation seen in some patients and contributed to delayed response and diminished efficacy. “Most of the problems were likely recovery from the surgical procedure and using a virus that doesn’t deliver any punch,” said Dr. Bennett.

An editorial in the NEJM by Alan F. Wright, MD, PhD of the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh sets a negative tone: “Without a highly efficient vector delivery system and sufficient surviving retinal pigment epithelium and photoreceptors, treatment success will be transient.”

But it’s ok for a treatment to be transient!

My mother underwent surgery, chemo, and radiation for breast cancer that wasn’t a cure, but it bought her 17 years. Drugs to treat diabetes, hypertension, acne, you name it, aren’t a one-shot deal. If I didn’t take a thyroid pill every day, I’d be dead.

Penicillin took many years to be developed -- so will gene therapy.

Penicillin took many years to be developed — so will gene therapy.

Dr. Pierce compares the trajectory of gene therapy to that of penicillin. “When it was introduced in the 1940s, not everybody responded, and we learned over time that we use different doses and routes of administration to treat different diseases. Should we have given up on penicillin? Call it bad because it didn’t work on everyone the first time we tried it? We needed to learn to use it effectively and develop additional antibiotics to treat what penicillin doesn’t. It will be the same story for gene therapy.”

Adds Dr. Bennett, “It would be naive to think that any drug is going to work perfectly all of the time. And it is also naive to think that we can immediately turn someone who is severely visually impaired to someone with 20/20 vision. We are still learning about the variables that determine success.”

Dr. Pierce thinks that the new findings are going to make gene therapy better in the long run. “People have been trying to develop treatments for LCA and related inherited blindness for 100 years. Nothing has ever worked before and here are the first set of therapies that actually work. It’s still a huge advance, but we need to perfect it.”

Given the difficulties of vector design and the pace at which gene transfer experts are learning to improve delivery, starting over would set back the clinical trial clock. And that would harm patients, said Dr. Bennett. “It would take another 15 years to get to this point and during that time a few more generations of affected individuals would go blind. There is something that works now!” A company, Spark Therapeutics has formed to commercialize the gene therapy developed at CHOP, and their website has several success stories. Dr. Bennett and her husband, ophthalmologist Dr. Al Maguire, who performs the procedures, have waived all rights to profit.

So what’s wrong with a treatment that must be repeated every few years in order to give a child sight? Nothing at all, says Kristin Smedley, a mom of two profoundly blind sons who would give anything for the chance at gene therapy. “Until other therapies are available, gene therapy is the best hope right now for my boys. Even if this approach only restores a fraction of vision, that fraction could mean no longer needing a cane to navigate or being able to read print instead of Braille.”

Michael Smedley

Michael Smedley

The Smedley family’s form of LCA is caused by mutation in a gene called CRB1. In March I attended the annual gala for their Cure Retinal Blindness Foundation. During the cocktail hour, someone was singing at the piano, “Born to Run.” I turned to my husband.

“Who would have the confidence to try to match Bruce Springsteen, and on that song? And sound just like him?”

Michael Smedley did. Blindness hasn’t stopped him from being a musician, an actor, and an athlete. I can hardly imagine what he will be capable of as an adult, when  he will likely, finally, be able to see. For gene therapy to vanquish CRB1-associated LCA is on Dr. Bennett’s short list. She heard him perform the Boss’s anthem too, followed a little while later by a sing-along to Don’t Stop Believing on an electric keyboard onstage in front of the packed ballroom. It was magical.

We can take a lesson from Michael Smedley and Journey. I’m all about science and not belief, but the families with blind children shouldn’t let the NEJM reports this week bring them down. Gene therapy for LCA works!

(A similar post appeared on May 4 at www.rickilewis.com.)

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AGTC Tackles 3 Eye Diseases with Gene Therapy

eyeSeptember will be 25 years since the first gene therapy experiment, and FDA approval is finally in sight. Several gene therapies are approaching the finish line, awaiting results from comparisons to existing therapies and analyses of long-term efficacy.

Among the contenders are:
lipoprotein lipase deficiency (already available in Europe)
childhood cerebral adrenoleukodystrophy (late clinical trials)
SCID-X1 (better than allogeneic stem cell transplant; more boys got better and did so faster)
Leber congenital amaurosis type 2 (RPE65 blindness mutation; late clinical trials, long-term effects published soon)

Next might be ADA deficiency, hemophilia B, and Wiskott-Aldrich syndrome, and just underway is giant axonal neuropathy. I’m sure I’ve missed a few.

Because thousands of single-gene disorders are theoretically candidate for gene therapy, yet only a few companies are shepherding treatments towards commercialization, I’m intrigued by how they choose their targets.

1 - Logo_AGTCApplied Genetic Technologies Corp (AGTC) is one such company that has carved its niche in “orphan ophthalmology,” focusing on a trio of single-gene disorders in which the photoreceptors do not degenerate: X-linked retinoschisisachromatopsia, and X-linked retinitis pigmentosa. Five experts in the use of adeno-associated virus (AAV) to deliver genes founded the company.

AGTC’s vectors introduce functional versions of mutated genes, enabling the targeted cells to produce the crucial proteins whose production the mutation impairs. The company recently announced collaboration with 4D Molecular Therapeutics to develop new AAV vectors.

(A note concerning the recent flurry of reports on genome editing using CRISPR and other technologies: Gene therapy as envisioned since the first trial in 1990 delivers functional genes that supplement the actions or inactions of mutant genes. It doesn’t replace mutant genes as genome editing does. Some reports mix these up.)

I spoke recently with AGTC President and CEO Sue Washer.

Several reasons. These diseases are very well understood at the cellular and DNA levels, and we know how a missing protein affects vision. Robust animal models have the same genetic defect as human patients. Screening and testing efficacy is straightforward. Unlike other orphan drug spaces in which companies and researchers spend a lot of time figuring out clinically meaningful endpoints to negotiate with regulators and do tests reliably, with ophthalmology, you know the endpoints: visual acuity, visual field, and contrast sensitivity.

Cones appear red in these retinal layers.  (Dr. Mark Pennesi)

Cones appear red in these retinal layers. (Dr. Mark Pennesi)


Using OCT (optical coherence tomography) you can see the layers of specialized cells in the eye. In a patient with XLRS, the layers are pulled apart because a protein is not there to hold them together. Because the layers of the retina are not talking to teach other, electrical signals when photons hit can’t get to the back of the eye, even though the photoreceptors function.

XLRS affects 35,000 males in the US and Europe. All patients have a mutation in the RS1 gene that produces structural proteins in the extracellular matrix that form complexes that interact with cell surface molecules. The only treatment is off-label use of carbonic anhydrase inhibitors – glaucoma drops. These dehydrate the back of the eye so the retinal layers lay down on each other, but results are anecdotal and it doesn’t always help visual acuity.

By intravitreal injection of AAV with the correct copy of the gene, transduced cells in the macula and fovea (the area of densest photoreceptors) send the protein into the space and pull the layers of the retina back together. AAV supports secretion of the normal protein for the life of the cell because retinal cells don’t turn over. We expect human phase 1/2 clinical trial data by the end of the year. The first few cohorts will be over age 18, but once the maximum tolerated dose is determined, we’ll expand to age 6.


Oliver Sachs’ book “The Island of the Colorblind” made achromatopsia famous. (A typhoon in 1780 decimated the population of the Pingelapese people on an eastern Caroline island, and when the population grew anew from a few surviving individuals, up to 10% of them became blind in infancy. (It’s a classic population bottleneck.)

Achromatopsia is more than colorblindness. In typical X-linked colorblindness a man has normal visual acuity but can’t see red or green. In achromatopsia all 3 cone types have no function and the person only has rod vision, seeing in black and white and shades of grey. (It is autosomal recessive.) When the lights are on, the person is completely blind. A person with vision going to the bathroom in the middle of the night and turning on the light can see because the cones turn on. In achromatopsia, they don’t. People are severely photophobic, legally blind, and even in a normally lit office building wear heavily tinted glasses. Outside they wear goggles.

In the US and Europe 28,000 people have achromatopsia. Half have mutations in the CNGB3 gene (cyclic nucleotide-gated channel type B3) and another 25% in the CNGA3 gene. Both encode proteins that form channels in cones through which photons enter. In achromatopsia, photons won’t trigger the cascade, interrupting the visual pathway. We are developing gene therapy for each type. A proprietary engineered promoter only allows gene expression in the cell membrane of the photoreceptors.

RP is a disease class caused by at least 150 different gene mutations. X-linked RP accounts for 10% of cases, and about 90% of them, or 20,000 people, have the RPGR gene mutation. RPGR (retinitis pigmentosa GTPase regulator) is a protein that helps the phototransduction cascade from the inner to the outer segments of the photoreceptors.

The disease affects the rods initially, but the cones over time. It is progressive, starting with nightblindness and then constriction of the visual field until by the 50s or 60s there is only tunnel vision. Later in life people lose central vision as well. We’re working with a dog model to deliver AAV and improve visual function in the dog’s eyes and are beginning dosage studies in non-human primates in preparation for a toxicity study. We will file an investigational new drug application next year.



Lower mammals – mice, dogs, and pigs — have retinal cells that use the same phototransduction pathway as primates, but the structure of the eye is different. They have no macula or fovea or inner limiting membrane (which separates the retina from the vitreous body), as primate eyes do. Mice have tiny eyes, highly disorganized retinas, and cell types that eventually spread throughout the retina.

When we select the capsid (viral protein coat), promoters (genetic controls), and physical delivery methods for human clinical trials of a gene therapy, we need to screen in non-human primates. Capsid and promoters that work astoundingly well in mice, dogs and pigs don’t work well in primates. So we need 2 sets of data: the lower animal model to see if the protein goes to the right place and can have a clinical effect, and primate data to show that we can get the protein to the right place. Having these two sets of data significantly improves chances of success in human clinical trials.

With all of the pieces that must fit exactly right for delivery of a gene to have a therapeutic effect, it isn’t surprising that gene therapy has taken a quarter of a century to get off the ground. In 2 weeks, DNA Science will revisit two incredible families about to embark on the gene therapy journey, if they can overcome potential problems posed by the immune system.

Eliza O'Neill has San Filippo syndrome type A.

Eliza O’Neill has San Filippo syndrome type A.

Eliza O’Neill and her family have been in self-imposed quarantine in their home in South Carolina for nearly a year, to keep her virus-free so that she might be selected for a clinical trial of gene therapy to treat Sanfilippo syndrome A.

(Dr. Wendy Josephs)

Hannah Sames has giant axonal neuropathy (Dr. Wendy Josephs)

Hannah Sames is not among the first children to participate in the clinical trial for giant axonal neuropathy that has just begun, and that her family largely funded, because she doesn’t make the missing protein. Her immune system might reject healing genes.

Stay tuned …

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Adventures in Stem Cell Land

The_snake_oil_serumTwo weeks ago a neurologist asked me to blog about a US-based company that is offering stem cell treatments, because it had raised hopes among some of his patients. Intrigued because I cover  “stem cell tourism” in my bioethics class and ask students to evaluate companies, I did a little poking around.

I’m questioning what appears to be a strategy to deceive desperate and vulnerable patients by offering stem cell treatments under the guise of participating in clinical trials. The company name isn’t important, because I suspect many others are doing worse. But their strategy, which may well be legal, is unethical.

First, some basic information. The Food and Drug Administration (FDA) approves drugs and medical devices for marketing. The National Institutes of Health (NIH) funds basic research and clinical trials, which can be registered at clinicaltrials.gov. Registering does not mean approval from either agency.

From the FDA: “At this time, there are no licensed stem cell treatments.” However, stem cells are the important parts of bone marrow and umbilical cord transplants to treat certain disorders.

From the NIH: A  registered trial may be observational, which means it doesn’t have to be randomized or controlled.

The company sells a procedure that extracts mesenchymal stem cells (MSCs) from a patient’s fat, separates out the stem cells, and then injects them where they’re needed. These stem cells are pluripotent — capable of several fates — and are very well-studied. Vet-Stem has been offering MSCs to treat injuries and degenerative conditions for dogs, cats, and horses for years.

Are patients receiving proven treatments, or are they guinea pigs in dubious clinical trials?

Are patients receiving proven treatments, or are they guinea pigs in dubious clinical trials?

Key words on the website include “superiority,” “advanced,” “excellence,” and of course “cutting edge.” But no mention of “experimental” or “investigational,” and to their credit, “cure.” The connection to clinicaltrials.gov uses the word “study.” Testimonials are prominent, but I prefer the dog and cat success stories” at Vet-Stem.

A company rep explained that payment for treatment is separate from participating in the clinical trial. He said this three times so it must be important in how they manage to legitimize what they sell. Assessment consists of self-reporting. I was reassured repeatedly that a PhD in neuroscience reads PubMed to determine safety and efficacy of studies supporting the company’s offerings. The other staff members are the surgeons who actually transfer the fat.

I picked up all sorts of errors on the website:

1. The use of the phrase “registered through the NIH” reverberates throughout, and is the fourth sentence of the opening page. Said the neurologist who contacted me, “Anyone can register a trial.” He has conducted dozens of them, real ones that is.

90270_web2. The definition of stem cell makes the common oversimplification error: “These cells have the ability to change or ‘differentiate’ into other types of cells.” No. The primary characteristic of a stem cell is its ability to self-renew. If a stem cell didn’t replicate, it wouldn’t be a stem cell. It begets another stem cell and usually a progenitor cell, which typically spawns increasingly specialized cells that ultimately produce a differentiated cell type. But a stem cell is always perpetuated, and that’s why moving stem cells about the body willy-nilly could, theoretically, trigger cancer.

3. Grammar. You don’t have “amounts of stem cells.” Numbers.

4. Regenerative medicine is not new. It’s been going on for decades. (Well, so has personalized medicine. It’s called genetics.)

5. Why use a patient’s own stem cells? Yes, the body won’t reject them. But they might re-introduce genes that contribute to the condition in the first place.  The name of the company includes the word “gene,” suggesting that this is a possibility. Or, it uses “gene” just to sound techy.

6. Where is the evidence, in large-scale, random controlled clinical trials, for efficacy of the“treatment” or “therapy?”

7. The list of treatable conditions is odd. They aren’t single-gene disorders. One folder denotes “autoimmune,” yet other folders are for multiple sclerosis, diabetes, and rheumatoid arthritis – classic autoimmune conditions.

8. Assessment is dubious. Treatment for COPD (which doesn’t make any sense at all to me) is assessed with a “quality of life” questionnaire a year after treatment, and for rheumatoid arthritis treatment success is judged by “participants’ assessment of their overall ability to be active.” How about something objective and measurable?

It is thinly-veiled pseudoscience.

I thought I’d investigate something I might one day have: osteoarthritis (OA) of the knee.

I already knew that dogs with OA of the hip had fared quite well with the very same treatment from Vet-Stem, in a randomized, blinded, controlled clinical trial. “Dogs treated with adipose-derived stem cell therapy had significantly improved scores for lameness, pain, and range of motion compared to control dogs,” the study found.

The news release from the human company about their new MSC treatment for OA announces collaboration with a Stem Cell Research Centre (SCRC). Nothing came up on Google. But it did appear at clinicaltrials.gov, on the very same entries, and from the very same city, as the stem cell company offering the treatments. Imagine that!

So I called.

Blubber harbors mesenchymal stem cells.

Blubber harbors mesenchymal stem cells.

America’s leading resource for stem cell therapy,” greeted me. I passed through layers of phone robots until a cheerful woman told me the cost for one injection of MSCs from my blubber into my knee: $14,900. I think I’d be better off at Vet-Stem.

Next I perused the medical literature since I, like the neuroscientist at the company, also have a PhD in a life science and enjoy reading a scintillating PubMed abstract now and then,

One recent study is from Seoul National University. The proof-of-concept investigation was a phase 1 (safety) trial of 9 patients given a low dose (10 million), a medium dose (5 million), or a high dose (100 million) of MSCs, injected into the knee joint. A phase 2 trial (efficacy) injected an additional 9 patients with a high-dose preparation.

At 6 months, “these results showed that intra-articular injection of [100 million adipose-derived] MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage,” the researchers concluded. In addition to self-reporting on a rating scale, the study used “clinical, radiological, arthroscopic, and histological evaluations.”

That’s promising, but 18 patients? More telling was a review article from the Biomechanics Laboratory at the Rizzoli Orthopaedic Institute in Bologna, Italy. Those investigators searched PubMed for all uses of MSCs to regenerate cartilage since 2002: 72 preclinical papers and 18 clinical trials, only two of which used adipose-derived MSCs. None of the trials was randomized, five were comparative, six were case series, and seven were case reports.

The reviewers conclude, “Despite the growing interest in this biological approach for cartilage regeneration, knowledge on this topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low-quality clinical studies.”

Even the preclinical studies aren’t all that promising. One from March in PLOS ONE, on a rabbit model of corneal graft rejection to improve on a mouse model, found that adipose-derived MSCs actually made matters worse.

$14,900 for a shot of my fat into my knee, based on this? If I was a racehorse, maybe.

Liposuction aspirate.

Liposuction aspirate.

Parts of the company’s offerings seem to add up to a legitimate whole.
• A surgeon can remove fat with mini-liposuction.
• A technician can separate stem cells or a soup containing them.
• A surgeon can inject stuff.
• The patient signs up for the procedure with quasi-informed consent and the self-report becomes part of a study registered at clinicaltrials.gov.

But how legitimate is it all?

Reading between the lines of the ClinicalTrials.gov Protocol Data Element Definitions, it appears that you can just make stuff up. It reminds me of when I registered my white Persian cat Angie and a friend’s llama many years ago as “Outstanding Young Women of America,”  for a newspaper column in the days before blogs. I can’t believe Google found it!

Is offering stem cell treatments that have not shown efficacy but are registered in trials building a house of cards?

Is offering stem cell treatments that have not shown efficacy but are registered in trials building a house of cards?

A study at clinicaltrials.gov requires a Human Subjects Review board, which includes an Institutional Review Board and an ethics committee. But “A study may be submitted for registration prior to approval of the review board so long as the study is not yet recruiting patients.

The entries from the company at clinicaltrials.gov are dated 2015,  so patients might not have been recruited yet, enabling them to legitimately use the phrase on the opening webpage, “IRB approved studies for stem cell treatments registered through The National Institutes of Health.” But I’ve signed off as an IRB for local high school science projects just because I have a PhD.

The company’s autologous fat stem cell offerings would fall under “procedure/surgery” and “genetic (including gene transfer, stem cells, and recombinant DNA)” at clinicaltrials.gov. I do have a call in to the NIH to clarify oversight, so will update this post when I can.

I hope that one day, infusions of one’s own stem cells will indeed hold at bay Parkinson’s disease, multiple sclerosis, rheumatoid arthritis, and other conditions. But until that time, hiding behind the cloak of government “approval” by registering an observational study with clinical trials.gov is unconscionable.

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Assessing Breast Cancer Risk: Beyond the Angelina Effect

JolieOn April 30 at 7:30 PM,  I’ll be part of a panel on Health Link with Benita Zahn, WMHT TV, to discuss the genetics behind the “Angelina Jolie effect” that has catalyzed testing for the BRCA mutations that increase risk for breast and ovarian cancer. It’s a tough assignment.

A letter in the current People magazine referring to Jolie’s recent announcement of the removal of her ovaries, following a double mastectomy last year, illustrates how at least one person is misconstruing the genetics of Jolie’s situation:

“How did she go about getting these types of tests and elective surgeries? It would be good to know if the same options are available for all women or if these procedures are something only afforded to the rich and famous.”


Angelina Jolie was tested and treated because of her family history, not her fame and fortune. Any genetic counselor or primary care provider would have been alert to her background: Her mother, grandmother, greatgrandmother, aunt, and a cousin had BRCA1-associated cancers.

That heritage places Jolie at far greater risk than most women. Mutations in the two BRCA genes account for only 5-10% of breast cancer cases and about 15% of ovarian cancers, according to the National Cancer Institute. Based on her family history, Angelina faced an 87% chance of developing breast cancer —  about five times the general population risk — and a 50% risk of developing ovarian cancer.

Two charts from the upcoming Health Link show will use the NCI data to compare lifetime risks for people with BRCA mutations to those of the general public. (The “lifetime” is important. An article in the Boston Globe recently made the common error of stating that 1 in 8 women has breast cancer.)


(Zeke Kubisch, HEALTH LINK, WMHT)

BRCA mutations are “germline.” That means a person is born with one mutated copy in each cell. With a second mutation in the gene, years later, in a breast or ovary cell, cancer develops. This “2-hit hypothesis” is from Alfred Knudson’s work in 1971, reflecting even earlier ideas and still fueling the delineation of multiple mutations unfolding as cancer progresses. However,  just the presence of one BRCA mutation disrupts messenger RNA production enough to increase cancer risk — a “one hit” effect.

But BRCA isn’t all there is to inherited cancer risk.




We each have two copies of the two BRCA genes (unless a very rare mutation deletes the entire gene). But as is true for all genes, our personal versions vary, because DNA is an informational molecule, a sequence of four nucleotide base types. These two giant genes can differ in many ways, only some of which increase susceptibility to cancer.

Three mutations – the founder or Ashkenazi mutations – are “pathogenic” and elevate risk considerably. Yet some other versions of either gene are “variants of uncertain significance” — a patient could learn her gene has an unusual sequence, but be told that it isn’t known whether or not it increases cancer risk.

The BRCA genes encode proteins that repair DNA broken in both strands of the double helix. That means DNA anywhere, not just in the gene itself, so the normal versions of these genes are part of the cell’s arsenal to limit DNA damage. Other proteins do this too, and the repertoire of repair proteins interact to protect the cell.

We can tier the risks. BRCA1 and BRCA2 mutations are the most dangerous, while mutations in other genes, such as ATM, TP53, CHEK2, and PTEN, confer a more moderate increase and are behind family cancer syndromes. But that’s not all. Variants of dozens of other genes contribute in still-little-understood ways that slightly elevate cancer risk.

I’ve recently written about all of these, so I thought I’d summarize the findings here. Skip to the end for a look at online cancer risk calculators.




A report in the April 7 Journal of the American Medical Association shows that how likely a BRCA mutation is to lead to cancer depends on where it is in the gene.

Timothy Rebbeck, an epidemiologist at Penn Medicine’s Abramson Cancer Center and colleagues, displayed the BRCA genes like maps of cities scattered among vast underpopulated areas, highlighting hot spots where meaningful mutations lie.

Trouble arises from the middle and the ends of BRCA1. The gene has 24 exons (the parts that encode protein). Mutations in exon 11, right in the middle, raise risk of ovarian cancer, while mutations at the tips raise risk of breast cancer. BRCA2 harbors three regions where mutations correspond to breast cancer and a different three that lead to ovarian cancer. Plus, mutations in different parts of the genes may influence age at onset. That’s important when weighing a decision to take a preventive measure that would affect fertility, or a treatment that has long-term adverse effects.

We don’t yet know how women will use this type of information. “If before testing a woman has a 50% risk and once she knows a particular mutation it changes to 60% risk, is that enough to change her pattern of behavior to prevent cancer?” asked Dr. Rebbeck.


Several companies, such as GeneDx and Myriad Genetics (known for the Supreme Court Decision about patenting the genes), have offered tests for the genes behind familial breast and ovarian cancer for years. They sequence entire genes as well as the most common mutations, including duplications and deletions.

Invitae_logo_h_light_bg_rgbA newer player is Invitae. “BRCA is just the beginning,” reads a banner on their website. For $1500, a physician can order pre-curated collections of up to 17 genes that confer risk to developing breast cancer, add another 17 cancer predisposition genes, or create a panel for a particular patient.

Removing total cost from the equation frees physicians to order tests based on a patient’s history and clinical situation. Plus, because all samples are tested for all the genes that the company covers, the physician can dip back into the data as a patient’s cancer progresses, seeking clues that might inform prognosis and treatment. A study from the company showed that doctors choose both pre-curated and customized test panels.


Genome-wide association studies (GWAS) take 2 populations differing by one factor, such as a disease, compare the DNA bases at millions of sites in the genome (single nucleotide polymorphisms, or SNPs), and see what the sick people have that the healthy ones don’t. GWAS results are associations, not causes. Another recent paper, in the Journal of the National Cancer Institute, reveals how analyzing SNPs can refine cancer risk prediction. (I wrote about it for Medscape.)

(Jane Ades, NHGRI)

(Jane Ades, NHGRI)

Celine Vachon, an epidemiologist at the Mayo Clinic and colleagues, used a “polygenic risk score” based on 76 SNPs identified in various GWAS, plus breast density, to predict risk among 334 healthy women. Women with the highest SNP scores and dense breasts had a 2.7-fold increased risk of developing breast cancer, and 11% of women previously classified as low risk were actually of higher risk, making them candidates for chemopreventive drugs, MRIs, and prophylactic mastectomy.

Most cancers are sporadic (non-familial), beginning with two mutations in both copies of a gene in the same cell, sometime after birth. The cause is an accident of DNA replication or a response to an environmental insult. The much rarer familial cancers tend to appear at younger ages because one cancer mutation is inherited, the other a consequence of later mutation in that first errant cell. The 2-hit hypothesis.

The idea that the environment can influence even the strongest genetic predisposition comes from a 2008 study. It found that average cumulative breast cancer risk to age 70 among women with BRCA1 mutations was 50% for women born between 1920 and 1929, but 58% among those born after 1950. Genetic change isn’t that fast.



Genetic counselors look for clues that a BRCA gene mutation may be at play in a family. They include:
• breast cancer in a man
• more than one type of primary cancer in one relative
• several generations with breast and/or ovarian cancer
• breast cancer in a person under 50
• cancer in each breast
• Ashkenazi Jewish, French Canadian (including Cajun), or Icelandic background.

Online Mendelian Inheritance in Man indicates other populations with elevated risk.

A genetic counselor would also consider other types of cancers in a family. BRCA1 mutations predispose to cancers of the cervix, colon, and pancreas, and BRCA2 to cancers of the stomach, gallbladder, pancreas and bile ducts, as well as to melanoma.

Even with lists of what to look for, BRCA mutations can go unnoticed for many generations, not causing cancer. That’s the case for my friend’s family. The 21-year-old son found out he had a BRCA1 mutation using 23andMe’s tests (when that was kosher), and we all assumed his mom, of Ashkenazi heritage, had passed it to him. But further testing revealed that his Catholic father had the mutation. Fortunately, no one in the family has cancer, although several relatives have refused to believe the test results.

I looked up my own risk using a few breast and ovarian cancer risk calculators. Everyone in my extended family has had cancer of some form, including me, except my sister. But the cancers were all late onset or due to some obvious environmental exposure, like my aunt the chain smoker and sun worshipper, my uncle the long-time radiologist, and me exposed to years of x-rays for orthodontia without appropriate shielding. My comparison is unscientific and apples-and-oranges, and some omissions,  like Susan B. Komen, adapt their tests from the NCI tool.

The Myriad calculator for having a BRCA1 or BRCA2 mutation gave me a risk of 8.2%.

The Penn risk calculator gave me a risk of 6% of having a BRCA mutation. It suggests anyone over 5% risk take a BRCA test.

The NCI’s Breast Cancer Risk Assessment Tool isn’t specific for the BRCA genes, includes some questions about reproductive history (important risk factors), but oddly, once I put in that I was white, did not give me the option to add Ashkenazi background. Still, it gave me a 14.3% risk of developing cancer by age 90 compared to the 8.6% of the general population. Glad to see lifespan extended!

The National Foundation for Cancer Research quiz looked only at age, and gave me a 284/100,000 risk for breast cancer, which they deemed “very high.” Huh?

Most helpful was the Bright Pink general breast cancer risk tool, because it asked everything. BMI. Exercise. Alcohol consumption. Breast density. Age at first period, first kid, breastfeeding. Family history.

Bright Pink provides a “report card” of sorts that tells you good things (“working in your favor”) so you don’t panic or feel helpless, then lists modifiable risk factors – things you can do to lower your cancer risk. I came out at “potentially high risk” and was advised to “see a doctor or genetic counselor to confirm that your baseline risk truly is only increased, and not actually high.” I appreciate the qualifiers.




Genetics is an imprecise science, and that’s why I try to use precise language. People develop cancer, they don’t contract it. The BRCA genes do not cause cancer, they elevate risk. I don’t even call people who have one BRCA mutation “carriers,” as is common, because as an old-school geneticist, carrier to me means recessive. The risk that inheriting a mutation imparts is dominant. It’s not hidden.

Some people with family histories riddled with cancer never develop it. And a person can be the only one in her family with a BRCA-associated cancer, never coming to the attention of a health care provider asking about family history — there is none. That’s what led Mary-Claire King, who discovered the mutations, to write a controversial viewpoint last fall advising population-wide screening.

Angelina Jolie has done a world of good by opening up about her actions to prevent the cancers that might have been her genetic destiny. But at the same time, her message that her family history is unusual may not have gotten through. According to Reuters, insurers are indeed balking at the increased demand for BRCA testing in the wake of Angelina’s messages. Genetic counselors are the experts who know the most about the complex issue of hereditary cancer, and can help to distinguish it from sporadic cases. See the National Society of Genetic Counselors to find help — and likely reassurance.

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Leroy Stevens: Fairwell to The Unsung Hero of Stem Cell Research

Leroy-Stevens1-230x300Yesterday a Google Alert popped up with a blast from my past, an obituary for Jackson Lab researcher Leroy C. Stevens. It quoted me calling him “The unsung hero of stem cell research” in an article I wrote 15 years ago for The Scientist. Dr. Stevens passed away on March 28.

Leroy Stevens was born in 1920 in Kenmore, New York, earned a B.S. from Cornell University in 1942 and a doctorate in embryology from the University of Rochester in 1952. I’d discovered his contribution while writing an article for The Scientist published on September 27, 1997, “Embryonic Stem Cells Debut to Little Media Attention.” Unfortunately the headline left off the word “human,” so hardly anyone noticed the article; hES cells blasted into public consciousness some 14 months later.

Back in those pre-electronic days, I trudged to the upper floors of the library at Albany Medical College, where I ironically teach online today, and found a dusty volume that held the treasures of Dr. Stevens’ serial images of developing mouse embryos.

IMG_1086The Scientist has graciously agreed to let me post my tribute from 2000. A more detailed version is in my essay book, “Discovery: Windows on the Life Sciences” (Blackwell Science, 2001). Many thanks to Anne Wheeler for permission to use the photos of her father. He spent his later research years developing mouse models to test chemotherapeutic agents. An update from her follows the post.

A Stem Cell Legacy: Leroy Stevens
The Scientist, March 6, 2000

When Science voted stem cell research its 1999 Breakthrough of the Year, the congratulatory article traced the field’s origin to the 1981 successful culture of mouse embryonic stem (ES) cells. But the roots of exploring these multipotential cells go back considerably farther, to a little-mentioned researcher who worked with mice at the Jackson Laboratory in Bar Harbor, Maine.

Leroy Stevens arrived at the lab in 1953, a newly-minted developmental biologist in a premolecular era when the tools of the trade were mostly one’s eyes. The young scientist found himself with an initial assignment that he calls “crazy.”

“The founder of the lab had gotten a grant from a tobacco company, and they wanted him to show that it wasn’t tobacco that was the problem–it was the paper in cigarettes!” recalls Don Varnum, a long-time technician in the lab. So Stevens dutifully dissected cigarettes and exposed mice to the components. One day, he noticed a mouse with a huge scrotum. “We killed it, and looked at the testes, and they had strange things inside.”

This teratoma from the chest has fat blobs, a tooth, a hair, and bone bits.

This teratoma from the chest has fat blobs, teeth, a hair, and bone bits.

The growth included a mishmash of tissue, including hair and teeth. It was a teratoma, and other mice of strain 129 had them too. Intrigued, Stevens pursued federal funding to explore teratomas, and the support lasted a professional lifetime. “This stuff was extremely interesting, and it sure beat studying cigarette papers!” he recalls from his home in rural Vermont, where he has lived near family since suffering a stroke 10 years ago.

Stevens bred strain 129 to select for the teratoma tendency. Then he developed a serial transfer technique to be able to continuously study the rare cells in some of the growths that rendered them cancerous. When and if a teratoma ran out of these “embryonal” cells, it would just sit there, sporting its peculiar mix of hair and teeth, cartilage, and tiny tubules. “We just wanted to keep the tumor alive longer so we could study it. But it took a long time to succeed,” says Stevens.

By passaging teratomas through many hosts and removing them from time to time and cataloging the tissues, the researchers witnessed all that these cells could become. And the odd tissue struggling for identity wasn’t as haphazard as it seemed. When Stevens and Varnum transplanted teratoma bits into the peritoneal cavities of mice, curious growths resembling inside-out embryos formed, called embryoid bodies. The tissues from the teratomas, given signals from the ascites fluid of the peritoneal cavity, seemed to be trying to organize.

The researchers continued to describe the tissues of teratomas and embryoid bodies, supplementing their publications with spectacular atlases of photographs that captured the temporal unfolding of this deranged development. Although the anatomy was clearly off, both out of place and out of time, Stevens and Varnum noted that the events followed a sequence of sorts. “Roy looked at thousands and thousands of mice. He noticed that for tissues to develop, several tissues must be in contact, so that the cells know whether to become liver or kidney,” Varnum recalls.

256px-JacksonLabsSignAlthough Stevens’ and Varnum’s work was purely basic research, the events that they so carefully chronicled, and the biochemicals from without and within that fueled the choreography of early development, are what stem cell researchers and tissue engineers are deciphering today.


With a steady supply of teratomas and their tissues identified, Stevens moved on to other questions–where, and when, did development take a wrong turn? And so he began looking backward, seeking the earliest stage when cells in the testes looked different, and then going back a few more days to account for changes not obvious to a human observer. This approach took him to the genital ridge in a 12-day prenatal mouse, which houses primordial germ cells, sperm precursors.

800px-Lab_mouse_mg_3140Then in 1970, Stevens made a leap that would profoundly affect stem cell technology a decade later–he noticed that the primordial germ cells that gave rise to teratomas looked a lot like the cells of considerably earlier embryos. So he transplanted cells from various stages of early strain 129 embryos, including inner cell mass cells (a very early embryo, minus the cells that become extra-embryonic membranes), into testes of adult mice. Some of the early embryo cells gave rise to teratomas! These induced growths looked and acted like spontaneous teratomas, yielding embryoid bodies when transplanted into mouse bellies and displaying an impressive range of tissue types.

Stevens called these cells from early strain 129 embryos that could support differentiation “pluripotent embryonic stem cells”–the origin of the term “ES cell.” But because these cells could give rise to cancerous as well as normal cells, they became known as embryonal carcinoma, or EC cells.

The rest, as they say, was history. But quite a lot transpired between Stevens’ identification of the developmental potentials of primordial germ cells and inner cell mass cells, and the unveiling of the role of the human versions of these cells as ES cells.

Human ES cells (NHGRI)

Human ES cells (NHGRI)

First, Beatrice Mintz and Karl Illmensee, from the Institute for Cancer Research in Philadelphia, visited Stevens to learn his techniques and borrow mice; then they demonstrated that ES cells could give rise to organisms, not just teratomas. (Their surprise announcement of this feat at a meeting floored Stevens, a story unto itself.) Then Martin Evans at Cambridge University and Gail Martin at the University of California, San Francisco, and their coworkers showed that inner cell masses from normal mice could support development too.

The field detoured into genetically altering mouse ES cells, which evolved into knockout technology with the harnessing of homologous recombination to target the genetic changes. Then in the late 1980s, Brigid Hogan, a professor of cell biology at the Vanderbilt University School of Medicine in Nashville, with Peter Donovan’s group at the National Cancer Institute, reignited interest in primordial germ cells by devising culture methods. These cells became known as embryonic germ (EG) or  embryonic stem-like cells.

It wasn’t until November 1998, with publication of the two human ES cell papers, that the media and public were finally diverted from Dolly the cloned sheep sufficiently to notice this much more powerful technology. Attention centered on the two cell sources, and still does.

James Thomson’s group at the Wisconsin Regional Primate Research Center used inner cell masses from in vitro fertilization clinic “leftovers,” while John Gearhart’s group at the Johns Hopkins University School of Medicine used primordial germ cells from aborted fetuses. And the work that led to their success began in a mouse lab nearly half a century ago, with a man with gifted hands and alert eyes who personifies Louis Pasteur’s oft-quoted observation that “chance favors only the prepared mind.”

P.S. A few words from Dr. Stevens’ daughter, Anne Wheeler:

Leroy old“My dad had a major stroke a few days before he retired. It took years for him to ‘come back’, but he did…much to everyone’s surprise. In the past 25 years, he must have been ‘near death’ at least 50 times…strokes, heart attack, bleeding ulcers, etc. He was tenacious, strong, had good genes (apparently!!), and I think his joie de vie, positive attitude and sense of humor brought him back each time. He finally died of congestive respiratory failure. He died peacefully in his sleep, luckily.

He lived on his own, cut his own firewood, had a garden until about 15 years ago. Then, he moved to a ‘retirement’ place where he lived on his own in his own cottage, until just 9 months ago, when he moved to a memory loss center. Every winter, we traveled to Florida (“not that interesting”- LCS), then Costa Rica and Belize. Watching monkeys, sloths, and the ocean waves were some of his favorite things in life.”

He loved being with his 7 grandchildren…lots of birthday parties, weddings, celebrations.”

I’m honored to have had the chance to interview and learn from this great man, who founded a field.

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Autism Gene Discovery Recalls Alzheimer’s and BRCA1 Stories

AutismDiscovery of a new gene behind autism cleverly combines genetic techniques new and classic.

Autism has been difficult to characterize genetically. It is probably a common endpoint for many genotypes, and is a multifactorial (“complex”) trait. That is, hundreds of genes contribute risk to different degrees, as do environmental factors. Research reports implicate either dozens of genes in genomewide sweeps, or focus on a few genes that encode proteins that act at synapses, such as the neuroligins and neurexins.

Taking cues from the fact that males with autism outnumber females four to one, females are more severely affected, and siblings of females with autism are more likely to also have the condition than siblings of affected males, a team led by Tychele Turner and Aravinda Chakravarti of Johns Hopkins University School of Medicine searched for candidate genes among 13 “female-enriched multiplex families” — FEMFs – that have two or more girls or women with severe autism. The study was published online March 25 in Nature.

Presumably, causative mutations in the female members of these families would have more severe effects. So identifying genes that stand out in their exomes (the protein-encoding part of the genome) and that make physiological sense – that is, affect the brain – could reveal general steps in the beginnings of autism in the broader population. The researchers describe their approach as “modest numbers of samples of rare extreme phenotypes, in contrast to large numbers of typical cases.”

Autism_awareness_ribbon-20051114EXPERIMENTAL RESULTS CONVERGE
The FEMFs indeed revealed 18 candidate genes, four of which emerged as the strongest. The researchers further tested the most likely gene, CTNND2, because it had turned up in other studies. CTNND2 encodes a protein called delta-2 catenin. A series of experiments then led to the following findings:

CLUE 1: Most mutations in humans delete all or part of the gene.

CLUE 2: Knocking out the gene in mice and zebrafish disrupts synapses. Therefore the mutation’s effect is a loss of a normal function, rather than a gain of a new function – and it affects neurons.

CLUE 3: The gene is expressed at 20 times higher level in human fetal brain cells than in human adult brain cells. (This is consistent with the fact that the brain changes that set the stage for autism begin prenatally.)

CLUE 4: The Allen Brain Atlas identified genes with which CTNND2 interacts. They include the usual suspects – proteins that act at synapses or in neural extensions, and in the actin cytoskeleton –  but also a new role, chromatin modification. This means that absence of CTNND2 protein would affect many genes, a broad stroke that could paint the many manifestations of autism.

armadillo(Aside: A key part of the CTNND2 protein is the “armadillo domain,” a 40-amino-acid repeat important in how an embryo passes signals from outside to inside the cell.)

The new autism study brilliantly uses a handful of unusual families to open a door to the inner workings of autism. Even though the news release calls the FEMF strategy a “novel approach” and “unconventional method,” it actually continues the tradition that first drew me to study genetics – severe or unusual cases that provide insights into disease mechanisms that affect many.

Two examples come to mind: Alzheimer’s disease and breast cancer.

Auguste Deter, the first recognized patient with Alzheimer's disease

Auguste Deter, the first recognized patient with Alzheimer’s disease

The first recognized case of Alzheimer’s disease was Auguste Deter, who began displaying bizarre behavior when she was in her late forties, in the late 1890s. She would scream piteously for hours, often in the dead of night, and traipse around cocooned in bedsheets, propelled by wild hallucinations and delusions. Auguste also had profound memory loss, unable even to write a simple sentence because she’d forget what had just been asked of her. Yet she had glimpses of self-awareness, saying now and then, “I have lost myself.”

Auguste’s terrified husband took her to the Institution for the Mentally Ill and for Epileptics in Frankfurt, where she came under the care of Dr. Alois Alzheimer in 1901. She died five years later, at age 56. In November of that year, after examining her brain, Dr. Alzheimer gave his now-famous lecture on her condition, which was published in 1911 as “eine eigenartige Erkrankung der Hirnrinde” (“a peculiar disorder of the cerebral cortex”).

Alois Alzheimer

Alois Alzheimer

Alas, Dr. Alzheimer’s meticulous and vivid description was lost to history, even as increasing lifespan revealed many people with forms of the condition that Auguste Deter had.

In 1996, psychiatrist Konrad Maurer rediscovered Alzheimer’s medical records for Auguste Deter, and published an analysis in The Lancet. A year earlier, a team from the University of Toronto had identified the presenilin 1 gene in some families with early-onset Alzheimer’s disease. Then in 2013, researchers discovered that Auguste Deter had a presenilin 1 mutation. (See Comment below, this paper is incorrect. Thank you reader!)

256px-BRCA1_enEven more so than the case of Auguste Deter, the new study on autism using female-enriched families reminded me of the 1990 paper in Science introducing the breast cancer 1 gene, better known as BRCA1. That study sought families enriched for early-onset breast cancer.

Mary Claire King famously trolled for susceptibility genes among 329 members of 23 extended families, who included 146 cases of early-onset breast cancer. For anyone who remembers LOD scores (“logarithm of the odds”), a statistic that shows linkage of a phenotype with a particular part of a chromosome, BRCA1 had a good one – 5.98 – signaling something amiss on chromosome 17. Since then, thousands of women and some men have had BRCA1 tests.

Alzheimer DiseaseThe newfound mutations in CTNND2 that may cause or contribute to autism are rare, as are mutations in presenilin 1 among people with Alzheimer’s disease and mutations in BRCA1 among people with breast cancer. But identifying these genes and their pathogenic variants, in the very few patients who serve as canaries-in-the-coalmine, can illuminate at the molecular level how these diseases begin and develop. And that’s a direct route to treating, or at least slowing or controlling, them.

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Universal Newborn Genome Sequencing and Generation Alpha

Newborn Screening

Imagine the day that genome sequencing of all newborns begins. Instantly two cohorts of people will form: the expanding youngest, with a tremendous amount of personal information stored on a cloud, and the shrinking rest of us, with little knowledge of our genomes.

A century from now, possibly everyone will have access to her or his genome data. But until then, how can we prepare to handle the avalanche of information about what I’d call, if I were a science fiction writer, “generation Alpha?”

My idea of the Alphas is inspired by the 1992 dystopian novel “The Children of Men,” by P.D. James. In 1994, all human sperm suddenly die, and 1995 becomes Year Omega. After that, populations plummet and age in the face of global infertility, with the last remaining people, the Omegas, struggling towards inevitable extinction.



What will happen in our world, in our society, as the Alphas age?


Mining sequenced genomes today has the very best of intentions: ending the “diagnostic odysseys” that patients, typically children with rare or one-of-a-kind diseases, endure. But just as opening a magazine can reveal much more than the article one is looking for, a genome sequence provides hundreds of thousands of gene variants that might mean something about a person’s health, perhaps things totally unexpected.

For now, to restrict dissemination of information to the meaningful, the American College of Medical Genetics and Genomics lists 56 “actionable” secondary findings, a minimal menu of genetic conditions which doctors can prevent or treat that show up while looking for something that could explain symptoms. The list will grow as more genes and their variants are identified, and these conditions have already outgrown their initial designation as “incidental.” They’re important.

Thousands of newborns have already had their genomes sequenced, as part of a handful of projects at major research centers. The actual deciphering can take under a day – a lot better than the decade required to sequence the first human genomes. But our understanding of how genotype becomes phenotype lags far behind the ability to decipher the sequence. The value of an “annotated” genome compared to “raw sequence” is like comparing the plot of To Kill a Mockingbird to a pile of word-size pieces cut from a copy of the book. When it comes to genomes, meaning and context are everything.

ATCG's Image with Group of PeopleBEYOND THE USUAL SUSPECTS

The era of looking for what we already know, the “round up the usual suspects” approach to gene identification and disease diagnosis, will gradually end as more human genome sequences and their interpretations are stored in clouds. Our algorithms will ultimately identify all possible gene variants and their interactions – and what they mean at the whole-body level, the phenotype.

My concern is not those “usual suspects,” the well-studied mutations that lie behind single-gene disorders: cystic fibrosis, sickle cell disease, Huntington disease. I fear the fuzzier genetic information. Genome-wide association studies, for example, identify suites of gene variants that signal a good chance that an illness will happen, but not with the power of a clinical diagnosis based on symptoms and biomarkers. The media often trumpet such findings with a false sense of certainty.

(Note on terminology: “gene variant” is a broader, more politically correct term without the negative connotation of “mutation,” which classically means “change in a gene” from the most common form [“wild type”] in a particular population.)

What I fear most isn’t the use of genome information in predicting or diagnosing disease, but in identifying the harder-to-follow, multifactorial traits that are molded by genes and the environment and therefore much more difficult to trace or quantify: intelligence, personality, temperament, talents. Each gene contributes a small amount and to a differing degree to characteristics that aren’t as neatly predictable as the single-gene, Mendelian disorders like the hemophilias.

Newborn_baby_in_hospital_by_Bonnie_GruenbergWill the idea of genetic determinism – that we are our genes – strengthen as the stockpile of genomic information swells through the population, beginning with the youngest? Will the practice become the ultimate example of paternalism, because newborns didn’t provide permission? As they age, can they choose not to know? Will that even be imaginable, as today it’s difficult to envision or remember a time without the Internet?

Choosing not to know will be especially difficult if others have access to genome information. And who should those others be?


Annotated genome sequences could guide pediatricians in troubleshooting problems, providing a powerful new tool in preventive medicine. At the first birthday, a microbiome analysis might identify children with tendencies towards certain conditions, or with insufficiently challenged immune systems.



Beyond infancy, will availability of genome information fuel stratification as DNA data better predict who is most likely to benefit from a scarce medical resource, and only the young have that information? Years from now, will I be denied a treatment unless I have my genome sequenced to show that I’m just as likely to benefit as a 16-year-old whose genome has been in the electronic medical record since birth?

In a few years, will posh preschools scan applicants’ genome information to select pupils? Will teachers use it to create compatible study groups, or to identify a tendency to bully and treat such a child like future criminals were punished in the dystopian future of the Tom Cruise film Minority Report?

Will standardized test scores be compared to DNA data to deduce whether students are working up to their potential? Will employers look for genomic red flags, the way they stalk Facebook now for evidence of stupidity? This blog has already discussed DNA and dating.


I’m not sure where all this is heading, but it is coming. Widespread newborn genome sequencing could happen within a decade, experts tell me.

Francis Collins wrote in the Wall Street Journal July 7, 2014: “Over the course of the next few decades, the availability of cheap, efficient DNA sequencing technology will lead to a medical landscape in which each baby’s genome is sequenced, and that information is used to shape a lifetime of personalized strategies for disease prevention, detection and treatment.

Is Dr. Collins’ view too narrow? Genome information can be used for purposes other than healthcare. After all, genetic genealogy is based on using landmarks in genomes to identify individuals.



Some may say genome data will be secure, we can control access, and limit how much an individual can know about her or his DNA. But did the top executives of Sony Pictures Entertainment last fall ever imagine that all of the company’s as well as their personal e-mails would rain down on the media from the great iCloud in the sky, in 8 humungous and mortifying data dumps?

At least it can be argued that Jennifer Lawrence’s naked photos wouldn’t have gone everywhere if she hadn’t  sent them to a supposedly safe cloud in the first place. But what about the 11 million customers of Premera Blue Cross, whose clinical records, bank account information, and social security numbers may have been released in a cyberattack in May 2014, reported in the media just two days ago?

Privacy breaches have already hampered DNA research. In 2013, Yaniv Erlich, from the Whitehead Institute and his astute student Melissa Gymrek demonstrated their ability to identify people who’d anonymously donated their DNA to the 1000 Genomes Project. They cataloged the short tandem repeats on Y chromosomes that are used in genetic genealogy and matched them to surnames and public information found on Google, such as state and year of birth. Cross-referencing to DNA sequences of cells at the Coriell Cell Repositories and more sleuthing led to women DNA donors. It’s in Science 339:321, unfortunately behind a paywall. And I’ve heard at genetics meetings about children identified by crossreferencing databases that name their rare diseases and their hometowns.

Is the cat out of the bag for genomes already sequenced?

Is the cat out of the bag for genomes already sequenced?

As with Jennifer Lawrence’s revealing images, DNA sequences will be out there, along with a lot of other identifying information. What can we do to ensure that a Sony situation, health insurance leak, or clever use of public databases doesn’t reveal DNA information on a large scale? Late last year Google took on inexpensive genome sequence storage, although raw data may initially be of limited value.

Can we adequately de-identify people and protect the very DNA data that will lay the groundwork for precision medicine? Will the Alphas be the guinea pigs for genome-control? Maybe precision medicine should stick to storing only clinically relevant DNA information. For now.

At a conference to be held April 8-10 at Children’s Mercy, Kansas City, several research groups sequencing newborn genomes as part of an NIH-funded program will meet to discuss results so far and how the information will be used and protected. That’s a great start to what will certainly be an intriguing and important conversation.

(A version of this post appeared on March 16 at the Biopolitical Times blog at the Center for Genetics and Society.)

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