GAN Gene Therapy Trial Gets Green Light

Lori and Hannah Sames (Dr. Wendy Josephs)

Lori and Hannah Sames (Dr. Wendy Josephs)

Last Friday, February 13th, Lori Sames couldn’t stop crying as she stared at her screen in a coffee shop near her home in Rexford, New York. The announcement had just gone up at clinicaltrials.gov: NCT02362438: Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy.

Finally.

Translation: recruitment for participants could begin for a clinical trial to test whether genes could be safely transferred into the spinal cord to treat, or at least arrest, a rare neurological disease, giant axonal neuropathy, or GAN. Lori’s 10-year-old Hannah has the disease, and if it weren’t for the family’s efforts, the clinical trial set to begin could still be many years away.

Lori and her husband Matt have raised more than $6 million to get the GAN clinical trial going, in a race against time to save their daughter Hannah and the other 70 or so kids and young people in the world with the disease. Early on they had selected gene therapy as the way to go.

HHFHannah’s Hope Fund was born in Lori and Matt’s home, shortly after the adorable kinky-haired little girl was diagnosed on March 24, 2008. She had just turned four. I’ve chronicled their journey at DNA Sciencehere and here, as well as in my book The Forever Fix: Gene Therapy and the Boy Who Saved It. Lori came up with “forever fix” during our first conversation years ago.

GAN is like ALS in a child. But people aren’t lining up to pour ice over each other’s heads to raise funds, for if ALS is a zebra amongst the horses that are common diseases, then GAN is a unicorn. The clinical trial announcement provides a good description:

The gigaxonin gene lets the body make a protein, gigaxonin, that nerves need to work. Giant axonal neuropathy (GAN) causes a shortage of functional gigaxonin. Nerves stop working normally. This causes problems with walking and sometimes with eating, breathing, and many other activities. GAN has no cure. GAN can shorten life. Researchers want to see if a gene transfer treatment may help people with GAN.”

hockeyHannah needs a wheelchair now, but she’s still very much Hannah. She beautifully sang the national anthem at several local hockey games in recent weeks.

In an ironic and cruel twist, Hannah won’t be among the first to receive the gene therapy. She has a double deletion mutation, one copy inherited from each parent, and so her body doesn’t make gigaxonin at all, not even an altered version of it. And so introducing healthy gigaxonin into her body could trigger an overwhelming immune response.

In the rare disease community, a triumph for one is a triumph for all. So this week before Rare Disease Day, I’d like to share a few comments about what Hannah’s Hope has accomplished.

From clinical trial director Steven Gray, PhD, from the University of North Carolina School of Medicine, at the annual Hope and Love ball for Hannah’s Hope, February 7:

None of this work would have occurred without the people in this room, and the entire Hannah’s Hope community… While we have come a long way, we have a long way to go. Hannah, and patients like her, who are unique in that they make no detectable protein, cannot participate in the Phase 1 trial. Studies are underway to try options for preventing her immune system from interfering with gene delivery. Also, as we learn more, we have more populations of cells we know we need to target in GAN patients beyond this initial delivery to the central nervous system.

From Lori Sames, announcing the start of the trial:

We will know in late April which immune tolerance protocol Hannah will receive, and we want you all with us, every step of the way. We believe in the power of positive thinking and ask that you focus your positive thoughts and prayers on those children who will soon be receiving gene delivery and on Hannah when she is injected, hopefully before the end of the summer.

Taylor King.

Taylor King

A web of shared experience, support, and hope closely connects the rare disease community. Laura King Edwards’ sister Taylor, 16, is battling Batten disease. Laura blogs at Write the Happy Ending and is writing a memoir about Taylor’s fight (it’s great, I’m an early reader).  She blogged recently about the link between Hannah and Taylor:

Nearly five years ago, when my sister could still sing and talk and walk and eat ice cream cones on hot summer days, my mother [Sharon King] met Steve Gray, a young investigator from the University of North Carolina Gene Therapy Center, at a conference in Bethesda. Since 2008 he’d been working on GAN, an ultra-rare, fatal childhood disease that causes progressive nerve death.

Laura King Edwards ran the Thunder Road half marathon blindfolded, in honor of her sister Taylor. Beside her is Dr. Steve Gray, PI of gene therapy trials for two brain diseases.

Laura King Edwards ran the Thunder Road half marathon blindfolded, in honor of her sister Taylor. Beside her is Dr. Steve Gray, PI of gene therapy trials for two brain diseases.

Months later, we drove to Chapel Hill to have dinner with him near his lab. We weren’t ready to take the leap then, but Mom had believed in Steve since the first time she heard him speak about his effort to save children from a monster that turned them into quadriplegics unable to eat or breathe on their own. When I sat across from Steve at our booth in a Franklin Street restaurant that day, I believed in him, too.

Our only mistake was that we didn’t fund Steve more quickly; it took Taylor’s Tale three years to sign on as co-funders of a project modeled after the GAN work, announced on World Rare Disease Day in February 2013. In doing so we followed in the footsteps of Hannah’s Hope Fund. Like my mother, Lori Sames entered the fight against GAN with no medical background. But Lori traveled the world, speaking to PhDs and MDs and biotech executives and raising millions of dollars in hopes of saving Hannah and kids like her.

Clinical trials happen all the time. But this one, for a little-known yet devastating disease that affects fewer than 100 children in the world, would never have happened without the dogged determination of Hannah’s family, who raised $6.5 million from their kitchen in upstate New York. It wouldn’t have happened without the genius and iron will of Steve Gray, who took an idea and turned it into a treatment in 6.5 years. This is light speed in the world of science, particularly for an ultra-rare disease like GAN.

Lori Sames at the Recombinant DNA Advisory Committee meeting.

Lori Sames at the Recombinant DNA Advisory Committee meeting.

I won’t forget the night Lori Sames flew to Charlotte to speak to the Taylor’s Tale board, or the day I took a long lunch to watch the webcast of my mother speaking on behalf of Hannah’s Hope Fund at the National Institutes of Health. That day, the Recombinant DNA Advisory Committee (RAC) granted approval for the GAN trial preparations to continue – a vital step in ensuring a better future for children with GAN.

I don’t think a rare disease has ever met a tougher match than Lori Sames or my mom. Lori and my mom looked their child’s rare disease in the face and said, “You will NOT defeat me. I will NOT sit back and let you take my child without a fight.” And because of the choices they’ve made, there is a light at the end of their respective tunnels.

We’ve poured everything into finding a treatment for infantile Batten disease since Taylor was diagnosed in 2006. I know Taylor’s Tale is a big reason why we are far closer to an answer today than we were then. But Taylor’s light is fading, and I’ve had to come to terms with the fact that the work we’re doing is for future Taylors.

I wish I could do more than send Taylor a hippo,

I wish I could do more than send Taylor a hippo.

So today, I try to focus on the good moments I’m able to steal with my sister. She can’t talk to me any longer, but sometimes I can make her laugh.

Hannah and Taylor are in the researchers’ minds when they’re in the lab, and I think that’s part of what drives them to be so good at what they do. I’ll never forget the first time I visited Steve’s lab at UNC. Photos of sick children decorate his office door. He told me that seeing the faces of those kids motivates him.

And though I understand now that we’re probably too late to save my sister, I still believe in this: that one day soon, because people like Steve Gray were motivated by the faces of kids on their office doors, kids like Hannah and Taylor won’t die young.

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Would Charles Darwin Have Used Tinder?

640px-Charles_Darwin_by_G._RichmondIn honor of Charles Darwin’s birthday today, and VD (Valentine’s Day) looming, I’m thinking about how we choose partners. A mobile dating app called Tinder, it turns out, seems to echo sexual selection, Darwin’s idea expounded in The Descent of Man.

This week’s timely post arose when my synapses connected an article just published in Nature’s Scientific Reports Journal, “Risk sensitivity as an evolutionary adaptation,” Darwin’s birthday, and the “Gray Matter” column in last Sunday’s New York Times by Eli J. Finkel, on Tinder.

The app is simple. Images of zillions of potential dates/mates appear on your phone screen. Swipe to the left to reject, swipe to the right to consider.

Judging_of_Best_Pig_in_ShowAfter observing a Tinder demo, the experience reminded me very much of scanning fruit flies for the phenotypes I was looking for. Or judging pigs at a state fair. Each of us likes certain physical traits, and avoids others. Why? What is the basis of attraction?

SETTLE OR WAIT? A DIGITAL EVOLUTIONARY SCENARIO
DNA Science last ventured into the dating arena with “DNA and Dating: Buyer Beware” a few months ago. So when a news release last week pitched “Evolutionary researchers have determined that settling for ‘Mr. Okay’ is a better evolutionary strategy than waiting for ‘Mr. Perfect,’ I was intrigued, with VD coming up. I requested the paper. (Alas I can’t reprint my classic  “If 50 Shades of Grey Had Been Written By A Biology Textbook Author” in honor of tomorrow’s big film debut here because it is far too titillating for the sophisticated readers of PLOS Blogs. But the link still works.☺)

“Risk sensitivity as an evolutionary adaptation” sets up a simulation in a population of digital organisms. The researchers are Arend Hintze, Randy Olson, and leader Chris Adami from Michigan State University and Ralph Hertwig, a psychologist at the Max Planck Institute for Human Development in Berlin. Hintze got the idea to place his imaginary creatures in an evolutionary setting from Hertwig, on visits home to Germany.

As usual the math in the paper scared me, so I zeroed in on the genetics, and found the study’s premise a little weak: “strong evidence that risk-taking behavior has significant genetic components.” Suspicious of genetic determinism, I checked out the two citations.

Gasterosteus_aculeatus_tüskés_pikóOne study refers to the genetic contribution to risk-taking behavior in the three-spined stickleback, a model organism. That paper, actually a book chapter, “describes some of the challenges in studying the genetic basis of individual differences in risk-taking behavior, arguing new insights will emerge from studies which take a whole-genome approach and which simultaneously consider both genetic and environmental influences on the behavior.” So the genomic link to risk-taking behavior, in fish or us, hasn’t yet been established.

The second paper is in the Quarterly Journal of Economics, but is indeed a genetic investigation. It’s a classic twin study (of humans, not fish) that found a heritability of 20% for “experimentally elicited preferences for risk and giving.” Heritability is often misinterpreted to mean the genetic contribution to a trait. Instead, it refers to the genetic contribution to the variability of a trait in a group. So 20% isn’t much.

But the hypothesis of a relationship between risk-taking and evolution is worth exploring, because we likely give a little more thought to mate choice, Tinder notwithstanding, than do fish.

To explore under what conditions mate choice is random or favors the evolutionary currency of ability to have fertile offspring, the researchers followed the choices of digital organisms put computationally through thousands of generations. (Here’s how you can adopt your own digital organism.)

They measured various things, such as conditions and group size. And they found that situations that prompt risk-taking are rare, perhaps once-in-a-lifetime, with a possible high payoff.

Each digital organism made one lifetime decision: 1 = “the safest gamble” or “live” and 0 = the opposite, death or failure to leave fertile offspring. If it lived, the digital organism passed its status (survivability) to offspring.

“Such a life or death decision is akin to a rare lifetime event that has a large
impact on an individual’s fitness, such as mating and mate competition,” the researchers write. The simulation included a low mutation rate, like in life, so that genomes could change and offer new fodder for selection.

ISHERB_Caveman The startling results were that the digital beings were less likely to take risks in collections of fewer than 150 or so – which gibes pretty well with the size of fledgling pre-human groups a million or so years ago. Experiments also simulated small groups within larger ones. “We found that it is really the group size, not the total population size, which matters in the evolution of risk aversion,” Hintze said. Dating in the neighborhood.

Adami translates the results into modern human behavior. “An individual might hold out to find the perfect mate, but run the risk of coming up empty and leaving no progeny. Settling early for the sure bet gives you an evolutionary advantage, if living in a small group. Primitive humans were likely forced to bet on whether or not they could find a better mate. They could either choose to mate with the first, potentially inferior, companion and risk inferior offspring, or they could wait for Mr. or Ms. Perfect to come around. If they chose to wait, they risk never mating.”

In contrast, with Tinder, one might hold out for perfection because the canvas of choices is huge and ever-expanding.

TELEOLOGY

Talk of evolution is often obfuscated by teleology, “the explanation of phenomena by the purpose they serve rather than by postulated causes,” says a standard definition. The phrase “evolves to,” for example, is a 4-letter word for us biology textbook authors, for it implies intent. Natural selection just happens, although it can be directional.

The digital organism paper, I think, has an underlying hint of teleology. The title of the first, unpublished version I read last week said “risk aversion,” which seems to have been changed to “risk sensitivity,” so perhaps the authors were aware of the issue of teleology.

Doubts aside, the findings got me thinking. I imagine myself, an australopithecine perhaps, living in a group of 150 or so, and dating. I’d be, say, 14 or 15 years old, approaching my peak fertility. Would I have had the mental capacity to evaluate who among my limited choices would most likely give me healthy, fertile kids? Do we have that capacity today?

Wading_mooseThat’s where sexual selection comes in, courtesy of Charles Darwin – the traits that attract us tend to be in fertile individuals. (See this article this article for relevant parts of the tome).

Sexually-selected traits are surrogates for fertility. It’s not as if a woman can peer through a man’s jeans into the labyrinth of his seminal vesicles to see whether his spermatids are maturing into healthy swimmers or not.

A female moose might seek a mate with big antlers.

A female 3-spined stickleback favors a male with a red throat.

800px-Bocca_ippopotamo_bioparcoAncient hippos living in what is now the UK grew to enormous lengths (64 feet!) because size seemingly mattered to the ladies.

So while the new study is intriguing in that it matches up the group size of 150 in affecting risk-taking choice with what’s known about early humans, I think the conclusion leads towards teleology – that we did what we did, and do what we do, for a purpose, to intentionally influence evolution.

ValentinesdaytreeI suspect Darwin might not have married his first cousin Emma had he been aware of the work of his contemporary Gregor Mendel. Or if he’d had Tinder.

Happy Valentine’s Day!

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Remembering The Pre-Vaccine Era: The Diseases of Childhood

poxMany of us of a certain age have vivid memories of the “diseases of childhood.”

We remember missing weeks of school, sky-high fevers, spots and pox, cheeks so puffed from mumps that eating was impossible, for days. Our mothers, for they did most of the parenting back then, would intentionally expose us to sick kids, so we’d get the scourges over with ASAP. The lucky among us made it through with just a pockmark or two.

I had the injected Salk polio vaccine as a toddler, but by the time my sister crunched her pink sugarcube of oral polio vaccine years later, I understood why vaccines were part of life. Protect many and you protect nearly all, because the infection can’t spread. It’s just common sense. Vaccination especially protects kids with chronic diseases, like cystic fibrosis, who can’t be immunized, as well as babies too young to have been immunized.

I posted my own “vaccine memories” last July, ending with research revealing a much more likely cause of autism than vaccines. For this post today, I asked a few friends about their memories of the diseases of childhood. First is Robert Marion, MD, a pediatrician at the Albert Einstein College of Medicine and chief of the division of genetics at the Children’s Hospital at Montefiore. He wrote one of my favorite books, Genetic Rounds: A Doctor’s Encounters in the Field that Revolutionized Medicine.

640px-Polio_vaccine_posterFROM A PEDIATRICIAN
“Until the last few years, the campaigns to immunize children against measles, mumps, rubella, diphtheria, pertussis, tetanus, polio, hepatitis B, Haemophilus influenzae, and others, have been so successful that most young pediatricians have never seen a single case. But these conditions were the bread and butter of pediatric practice prior to 1960.

The measles-mumps-rubella (MMR) vaccine was developed in the early 1970s, but each of the components was developed in the 1960s. Rubella (German measles) vaccine in particular was developed because of the devastation of congenital rubella.

Throughout the mid 20th century, epidemics of rubella raged every couple of years. Although the disease itself was mild, pregnant women contracting the virus were at risk to have children with deafness, blindness, congenital heart disease, failure to thrive, intellectual disabilities (then called “mental retardation”), and….yes, you guessed it…..autism. How ironic is it that the vaccine developed to prevent the leading cause of autism became the focus of this pseudoscientific crusade to prevent all humans from using vaccines? Pretty amazing, huh?

We see a fair amount of pertussis because it causes its real harm in very young children, before their full course of immunizations is complete. This is a life-threatening illness in infants, who cough so much that they can’t take in air. They’re at risk to develop hypoxic-ischemic encephalopathy, permanent brain damage, as a result, and every year, there are deaths from pertussis in the very young. About 10 years ago, I learned first hand that the pertussis vaccine does not bring life-long immunity. My son, a teenager, developed whooping cough and required intensive care for a few days. Not a lot of fun.

When I was an intern in the winter of 1979-1980, I cared for an adolescent girl who was brought into the hospital by ambulance, comatose. A few hours earlier, she’d complained of a headache, low grade fever, and became lethargic, confused, and finally unresponsive. Just like that. Seemingly out of the clear blue.

When we examined her, we noted healing scabs on her trunk and legs. On questioning, her parents (who spoke little English) let us know that she’d recently gotten over chickenpox. ‘But that was over a couple of weeks ago,’ they told us, implying that that illness couldn’t possibly be related to this illness. Of course, it was.

She had post varicella encephalitis, a rare complication of chickenpox. This poor girl’s CT scan showed cerebral edema with loss of myelin. Her spinal tap showed increased intracranial pressure.

We admitted her to the ICU. We put a bolt in her skull to measure her intracranial pressure. We treated her aggressively to keep the pressure in a tolerable range, so that her brain would continue to be perfused with blood, giving her mannitol (a powerful diuretic) every time her intracranial pressure spiked. We stayed on top of her.

She remained in this state, in the ICU, unresponsive to all but the most painful stimuli, for about five days. She then started to “lighten up,” raising her level of consciousness. Her intracranial pressure normalized and we were able to remove the bolt. One week after admission, we transferred her from the ICU to the medical floor.

Measles

Measles

The girl remained in the hospital for nearly a month, and then she was transferred to a pediatric rehab hospital. Because of the demyelination, she had lost significant muscle strength and wasn’t able to walk, barely able to sit up on her own. According to her parents, she had regained many of her cognitive skills, but when she left, they told her that she still “wasn’t herself.” I never saw her again, so I’m not sure whether she ever regained all of her function. But it’s clear that all of this could have been avoided had there been a vaccine.”

FROM NON-DOCS

Even routine cases of the childhood diseases were, at the very least, disruptive. Even if a kid wasn’t particularly ill, the disease spread.

“I had chickenpox in the third grade. I got hundreds, in my nostrils, in my throat, on my scalp, everywhere inside and outside. I couldn’t blink without it hurting. I wore gloves at night so I wouldn’t scratch my face. I couldn’t swallow, so I couldn’t eat. When I was finally better and put on shoes, they were too big because I’d lost so much weight. It was horrific. I was 8.” Sharon P., lawyer in NYC

“In 1960, when my father, who had a withered leg from polio, and my mother took me and my sister to get our oral polio vaccine, a line snaked around the block. Every kid in the neighborhood was there and nobody, but nobody, was talking about not getting it.

In high school, I caught rubella and wasn’t sick, just covered with red dots. It was the last day of the school year and I wanted to get stuff from my locker. On my way out, I stopped to say goodbye to my favorite English teacher. I told her I had German measles, thinking it was a sort of joke, and she just shrank away from me and whispered, “I’m pregnant!” I rushed out of the room and went home and stayed there. I felt awful and never saw her again.” Jennie Dusheck, science writer

“My sister and I both got measles midsummer. We were confined to our bedroom. Mom had to keep the drapes closed and we had to wear sunglasses to protect our eyes. I remember all the red splotches and being very itchy and some sort of lotion being applied. We stayed in that room for 7 days, with high fevers, not feeling well at all, and sleeping a lot. It’s hard to believe any parent would want to put their child through that!

Mumps_PHIL_130_loresI didn’t get mumps, but my mother did! It was during May of my senior year in high school. I had a huge term paper due and Mom was going to type it. I was also preparing to go to my senior prom, and give a speech at the National Honor Society induction ceremony. The day before that event, Mom started to get swelling in her face and throat, but the day of the induction ceremony she wrapped a warm scarf around her neck and attended. She could have infected lots of folks by being there. She went to the doctor’s after that and got the mumps diagnosis, and then was instructed to stay in the house. And she did type my paper!” Phyllis Kovall, music teacher

I don’t usually resort to name-calling, but in the case of refusing vaccines, I bow to a New Yorker cartoon by e. flake that shows a doctor examining a spotted child, in front of two befuddled parents: “If you connect the measles it spells out ‘My parents are idiots.’”

Indeed they are. It isn’t cool to be anti-science, or anti-medicine. It’s dumb. And deadly.

UPDATES

eman and flagsI was gratified to read in The New York Times, The New Yorker and elsewhere about the self-appointed neighborhood public health groups in Liberia who have slowed and possibly halted  the Ebola epidemic. Emmanuel Gokpolu, my young friend in Liberia, led one of those efforts, chronicled in How Ebola Kills and previous posts.

pink-150x150DNA Science covered use of mitochondrial DNA from a third party to create embryos free of mitochondrial disease nearly a year ago, when researchers debated the controversial technology at an FDA hearing. The news this week isn’t about the science, but about renewed discussion in the UK. I’ll get back to mitochondria soon, about a way to possibly fight mitochondrial disease without tinkering with embryos.

 

 

 
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Surveying the Genomic Landscape of Modern Mammals

A rhesus macaque and a Tasmanian devil.

A rhesus macaque and a Tasmanian devil.

A study published today in Cell  compares regulatory DNA sequences among 20 species of modern mammals, showcasing how mammalian genomes have found new uses for ancient genes.

The evolution of mammals has been ongoing for about 180 million years, with a burst of numbers and diversity about 66 million years ago. Then, an asteroid impact led to mass extinctions, and the small, scurrying, hairy ones found vacated real estate.

(NHGRI)

(NHGRI)

Fossils help in studying past life, but even more useful is to compare DNA sequences among modern species. The more of a gene or genome sequence a pair of species shares, the more recently they shared an ancestor. That is a more likely explanation for similarity at the DNA level, I think, than that two species ended up with nearly identical sequences by chance. And if researchers know the mutation rate for a specific gene, then they can assign approximate time frames to species’ divergence.

DISSECTING REGULATORY SEQUENCES
Diego Villar, from the University of Cambridge Cancer Research UK, Paul Flicek, head of Vertebrate Genomics at the European Molecular Biology Lab EMBL-EBI, and their colleagues identified promoter and enhancer regions in DNA from liver cells from the selected 20 species of placental mammals.

Promoters are short sequences at the starts of genes that control their transcription into RNA, from which protein is translated. Enhancers are short DNA sequences, typically located a bit away from the genes that they control, that bring different genes together as the chromosome unwinds and loops about itself. So both promoters and enhancers control gene expression, one from near, one from afar.

Tree shrew (wikispecies)

Tree shrew (wikispecies)

The list of participating mammals in the study is diverse, but heavy on primates, rodents, and sea dwellers: human, macaque, vervet and marmoset (primates); mouse, rat, naked mole rat and guinea pig (rodents); dolphin and two whales (cetaceans); and rabbit, tree shrew, pig, ferret, dog, cow, cat, opossum, and Tasmanian devil.

The researchers discovered that promoters tend to have evolved recently – which means over the past 40 million years. In contrast, most enhancers are derived from sequences that have been around for more than 100 million years, but have been co-opted to take on new functions. So species and their genomes can retain what’s worked in the past via natural selection, but can also tap into ancient sequences for new uses.

I’d use the word “repurpose” to describe enhancers’ links to past DNA, but “purpose” is a banned word in evolutionary biology, because it implies intent, which implies a creator. The researchers use the slightly less teleological “redeployment of ancestral DNA.” This approach is different from the gene duplication route to microevolutionary change I learned in graduate school. In that model a gene doubles, perhaps by a slip during DNA replication at a short repeated sequence, and then one copy, through mutation, acquires a novel function that persists if it does no harm.

An evolutionary success

An evolutionary success

It’s reassuring that a genome has more than one way to change, because that’s what evolution is: change. It is not directional, not leading towards someone’s concept of perfection, and we are certainly no more highly evolved, whatever that means, than a bacterium or cockroach. They’ve been around a lot longer than we have.

In 1982, Stephen Jay Gould and Elizabeth Vrba coined the term  exaptation to distinguish novel use of old information from natural selection, which instead results in an adaptation (a trait that makes it more likely to leave fertile offspring.) Exaptation is a little like what my daughter Heather says whenever I want to buy new furniture. “Use something already in the house.

My husband Larry demonstrating his exaptation of kitchen tools to capture rodents. He is a retired chemist with nearly 100 patents.

My husband Larry has exapted kitchen tools to capture rodents. He is a retired chemist with nearly 100 patents.

ALTERNATE VIEWS OF EVOLUTION
Some popular explanations of biological diversity do not take advantage of the endless information to be mined from DNA sequences. Consider the appearance of everything living within the span of a week, plunked down on the lovely Earth by a supernatural force.

According to Genesis, on day 5, God said, “Let the water teem with living creatures, and let birds fly above the earth across the vault of the sky.” Day 5 would seemingly cover the dolphin and pair of whales featured in the Cell paper, but the biblical description is classification by habitat, so includes fish and birds too.

bibleLet the land produce living creatures according to their kinds: the livestock, the creatures that move along the ground, and the wild animals, each according to its kind,” sayeth God on day 6. Towards the end of that great day, we humans came along to lord over everyone else, a situation evidenced by the terms “livestock” and “wild,” a somewhat more subjective taxonomy than comparing DNA sequences and mutation rates. Presumably this day would include the other species in the Cell paper not yet specifically mentioned.

Another skewed view of evolution is the common line-up of creatures, with humans coming after chimps as the most “advanced” species. Cartoonists sometimes put stooped-over office workers in the final slot, or someone hunched over a cell phone. These alignments are offshoots of the “Great Chain of Being,” a religious ordering of everything in the universe.

HaeckelBut evolution tends to be branching, not linear. We share an ancestor with chimps, from around 6 to 7 million years ago, but we didn’t morph directly from them. Even when a lineage appears to be linear, likely offshoots died out along the way, perhaps leaving a bit of themselves lurking in modern genomes, like the Neanderthals.

So now I’ve angered the anti-GMO folk in last week’s post, and the intelligent design crowd in this week’s post. Perhaps I should take next week off.

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From GMOs to GROs: Will Life Find a Way?

openerA pair of papers in this week’s Nature introduces GROs — “genomically recoded organisms” — whose altered genetic code makes them require a synthetic amino acid to survive. Although this new type of biocontainment indeed keeps microorganisms from spreading to where they aren’t wanted, at least in a lab, I don’t think the approach is likely to convert many anti-GMO folks to biotech fans, based on my experience.

ROTTEN TOMATOES
Several years ago, I spoke about genetically modified organisms (GMOs) to a group of citizen environmentalists, my goal to explain the precise procedures behind the vague term “genetic engineering.” Alas, the audience rapidly nodded off as I distinguished a transgenic organism from a knockout. They didn’t believe my tale of the first GMO released to the environment, “ice-minus” bacteria, that were sprayed onto strawberry plants by Advanced Genetic Sciences in 1987 to block ice nucleation. Activists destroyed a treated strawberry patch, unaware that the GM bacteria actually lacked a gene, rather than harboring a foreign one.

Unlike these unadulterated tomatoes, the  FlavrSavr failed not because it was genetically modified to have a long shelf life, but because it tasted bad.

Unlike these unadulterated tomatoes, the FlavrSavr failed not because it was genetically modified to have a long shelf life, but because it tasted bad.

The audience woke up, and became enraged, when I stated that traditional breeding is less precise than genetic manipulation. They yelled over my insistence that the same DNA triplets encode the same amino acids in all species. So unpleasant was the anti-science sentiment that I vowed never to speak about GMOs again.

My experience revealed that people fear GMOs – particularly plants – for a biological reason and an ethical reason:

#1: GMOs are perceived as not as safe to eat as unaltered vegetables and fruits.

#2 Any genetic manipulation beyond crossing and breeding is just wrong, an assault on nature.

Back then there was less concern about GMOs forcing reliance on certain herbicides and pesticides, and of “escape” to fields beyond where they’re intended to grow, two objections with which I agree.

TRIPLE-HEADED PURPLE MONSTERS
When I was in graduate school for genetics in the mid 1970s, the dawn of modern agricultural biotechnology, my mentor Thom Kaufman dubbed the unfounded fear of anything involving DNA the “triple-headed purple monster” mindset. It persists.

Even decades since we began regularly eating GMO crops, fear of their danger lingers. A January 17 article in the Washington Post proclaims “Over 80 Percent of Americans Support Mandatory Labels on Foods Containing DNA,” possibly the most idiotic headline of all time. Ever had a burger or banana that doesn’t contain DNA? All organisms do. And all use the same genetic code.

Golden rice is genetically modified to produce beta-carotene, upping vitamin A levels.

Golden rice is genetically modified to produce beta-carotene, upping vitamin A level.

I can’t fathom why people vehemently object to GM corn and soybeans, but not to vaccines and pharmaceuticals consisting of recombinant DNA translated into protein in non-human cells. Does anyone find offensive the candidate Ebola vaccines and drugs that include genes from different viruses grown in tobacco cells? “You Won’t Believe How They’re Growing the Ebola Vaccine” shouted another recent headline, above an article that repeatedly refers to “a bacteria” (that’s plural), and confuses bacteria with viruses. I wrote about producing recombinant DNA-derived proteins in tobacco plants in “Building a Better Tomato” in High Technology magazine, circa 1984.

The fact that 80% of those polled are demanding labels announcing the presence of DNA in their food confirms that the palpable fear and anger I felt years ago still simmers. And if that’s so, then the new studies about altering the genetic code may ignite a firestorm, despite the initial news emphasis on the fact that GROs have a genetic “safety lock.”

INTRODUCING GENETICALLY RECODED ORGANISMS
The Nature papers are a bit hard to follow, and require familiarity with the genetic code. It is the 64 possible mRNA triplets (codons) that are combinations of the four types of RNA bases (uracil, cytosine, adenine, and guanine), which are complementary to 64 types of DNA triplets. Of the 64 RNA codons, 61 encode any of 20 types of biological amino acids, and 3 mean “stop”: UAA, UAG, and UGA. A protein being synthesized along an mRNA molecule is complete when it encounters a stop codon. UAA, UAG, and UGA spell “stop” in all organisms, as well as in viruses. (Disclaimer: I have a UGA stop codon tee shirt.)

George Church of Personal Genome Project fame, who is the Robert Winthrop Professor of Genetics at Harvard Medical School, and colleagues report in the January 21 Nature that they replaced UAG “stop” codons in E. coli with UAA codons altered to bind and insert a “nonstandard amino acid” (NSAA) into a growing protein. An NSAA is not among the 20 that the natural genetic code specifies. The result is a GRO: a genomically recoded organism. It can’t survive without the NSAA.

“We now have the first example of genome-scale engineering rather than gene editing or genome copying. This is the most radically altered genome to date in terms of genome function. We have not only a new code, but also a new amino acid, and the organism is totally dependent on it,” said Dr. Church in a news release.

The genetic code. (NHGRI)

The genetic code. (NHGRI)

By swapping in the altered UAAs at many places in the bacterial genome, plus required tRNAs and “computationally redesigned” enzymes, protein synthesis incorporates the unnatural amino acids. As a result, DNA can’t move from cell to cell aboard viruses and other mobile DNA elements (horizontal gene transfer) or be replicated and passed to the next generation (vertical gene transfer), unless the NSAA is present.

Dr. Church calls the feat “irreversible, inescapable dependency.” All of this work is in very early stages and uses the standard E. coli and its T viruses, the stuff of classic molecular biology experiments from the 1960s and 1970s, and the microorganism in which many biological drugs are “pharmed.” It is a long way from being applied to fields of rhubarb.

GROs made their debut in a 2013 paper in Science from Dr. Church’s group, and were a candidate for the magazine’s “breakthrough of the year” in 2014. The 2013 paper describes the ability of GROs to resist viral infection, because they can’t be make viral proteins, as infected cells normally would. Viral infection can be disastrous for producing biopharmaceuticals or bioremediation agents.

In the second article on GROs in this week’s Nature, Farren J. Isaacs, an assistant professor of molecular, cell and developmental biology at Yale University, who did postdoctoral research in the Church lab, and colleagues describe retooling the UAG stop codons where they naturally occur in E. coli, but also introduce them into several essential genes. Their bacteria require two unnatural amino acids.

Dr. Isaacs and the Yale team also published an article with a headline I did like, “Multilayered genetic safeguards limit growth of microorganisms to defined environments,” in Nucleic Acids Research online January 7. They colorfully describe their multi-pronged approach as including “engineered riboregulators that tightly control expression of essential genes, and an engineered addiction module based on nucleases that cleaves the host genome.”

A NEW ROUTE TO BIOCONTAINMENT
In microbiological terms, a GRO is a “synthetic auxotroph.” Like bacteria before it genetically modified to resist an antibiotic or require a nutrient in order to survive, thereby providing a means of selection, the new breed of GROs depends on the NSAAs in the environment to make proteins, to stay alive and reproduce. A GRO can’t escape to where it isn’t wanted if it can’t get its NSAA.

In contrast to insecticide- or herbicide-resistant GMOs forcing reliance on a big company’s products, GROs work when something unnatural is not available in the environment. So they’d grow where the NSAA is, but not where it isn’t — if the technology ever extends beyond closed laboratory situations.

1024px-Jurassic_Park_4WD_and_dinosaur_at_Islands_of_AdventureWherever GROs end up, the researchers hope the altered genetic code will enable them to circumvent nature’s ways of surviving. New detoxifying mutations won’t help, for there is no toxin. Nor can natural selection or even horizontal gene transfer remove the altered codons. And GROs can’t suck up useful nutrients from neighbors – they need those NSAAs. But as mathematician Ian Malcolm pointed out in Jurassic Park, where genetically altered dinosaurs ran amok, “nature finds a way.”

256px-X-Files_Dana_Scully_CosplayBiocontainment based on altering the genetic code is an idea that was unimaginable back when such measures were first hammered out at the Asilomar conference on recombinant DNA held in 1975. In the 1990s, Dr. Dana (“I’m a scientist!”) Scully from the TV show The X-Files waxed melodramatic about a 5-base genetic code introduced by space aliens. It happens.

While GROs extend the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, the new papers are more proof-of-concept than practical, for now. None of the trillion E. coli that the Church lab grew over two weeks bolted. That’s “10,000 times better than the NIH recommendation for escape rate for genetically modified organisms,” Dr. Church said.

1000px-Mad_scientist.svgTHE MEDIA RESPONSE TO GROs

I eagerly awaited the media response to the reports on GROs, anticipating an uproar if the news aggregators went beyond the cautious news release to borrow phrases from the papers such as “whole organisms capable of sampling new evolutionary landscapes” and “reliance on synthetic metabolites.” Altering the genetic code is HUGE, a much more profound change than boosting beta carotene levels in rice or creating tomatoes with longer shelf lives, traits that result from single-gene changes.

The media coverage, so far, has been far less than I anticipated, with the usual suspects – the New York Times, Science Daily – doing a terrific job. But it wasn’t the stuff of CNN or the NBC evening news, and stories such as underinflated footballs, a cop singing along with Taylor Swift, and the arrest on corruption charges of the speaker of the New York State assembly, naturally got more coverage.

What would the anti-GMO organizations, places I don’t ordinarily visit since my traumatic lecture experience, say?

Greenpeace was concerned mainly with polar bears and whales. But GMO Awareness was apparently unaware that researchers had rewritten the genetic code and applied it to bacteria in a technology that could, someday, be used to reign in errant altered crops. The “breaking news” on their website is from October, and the featured story on their Facebook page concerns all-natural burgers, which I suspect in fact harbor some DNA.

It’s possible that the environmental groups do not yet comprehend the significance of what synthetic biology can do, or understand how it works. But maybe I’m wrong about that. Give it a few weeks.

Many questions remain, especially if GROs transition from initial roles in bioremediation and specialty chemicals and pharmaceuticals to food production. Will the NSAAs harm health if eaten or spread in the environment? Will the approach work for plants, which are so much more complex than E. coli?

As for me, I was recently asked again to speak about GMOs, in an adult education course next fall. I initially said no. But these two papers are so exciting that I’ve changed my mind.

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New Miracle Drugs: What Would You Pay?

Levi Collazo, before and after Kalydeco treatment for cystic fibrosis.

Levi Collazo, before and after taking Kalydeco for CF.

Levi Collazo, a biology major at Southwestern Oklahoma State University, has cystic fibrosis (CF).

“In the first photo, I was making fun of my own weight. I’ve always used humor as a defense mechanism. I weighed 110 pounds. I’m 5’10”. After taking Kalydeco for 2 years, I’m up to 148 pounds,” he wrote on the Facebook page Kalydeco Miracles.

The success of Kalydeco for some people with CF – “K” to its fans – is astonishing. The drug corrects misfolding of the CFTR protein that certain mutations cause.

THE STORY OF ‘K’
When the daily pill, developed by Vertex Pharmaceuticals, came on the market in 2012, only the 2,000 or so patients who have a specific mutation could use it. The drug cost $294,000 a year. Since then, further clinical trials have swelled the patient pool to about 3,100. The FDA approved the drug for a tenth mutation December 29, 2014.

Families still fight insurance companies for coverage, but the Cystic Fibrosis Foundation has funded development of Kalydeco and recently sold royalty rights, and is using the $3.3 billion to help patients and fund further research. With 75,000 people in North America, Europe and Australia having CF and trials on extension to other mutations continuing, the market may increase, and perhaps the price decrease.

Madi Vanstone, age 12, learned in June that the Ontario Drug Benefit formulary would cover the cost of her K and of everyone else’s in the province with a treatable mutation. Before that, insurance had been paying half of the $348,000 annual cost and Vertex 30%, leaving $60,000 for the family to cover. Without daily K, Madi would have needed a lung transplant in a few years and might not have survived her teens. Now, she has a future.

What would you pay to treat a debilitating and deadly disease?

Over the past few months, we’ve seen incredible price tags for groundbreaking new medical treatments.

Glybera is the first gene therapy approved in the western world. It treats lipoprotein lipase deficiency.

Glybera is the first gene therapy approved in the western world. It treats lipoprotein lipase deficiency.

GLYBERA, THE FIRST GENE THERAPY
Like Kalydeco, Glybera debuted in 2012. Amsterdam-based company UniQure with partner Chiesi make Glybera, the only approved gene therapy in the western world.

Glybera treats painful and lethal lipoprotein lipase deficiency (LPLD). The price in Germany, announced in late November, set a new record for a medicine to treat a rare disease: $1.4 million for the one-time series of 42 intramuscular injections that should banish the disease.

In LPLD triglycerides build up in the pancreas, liver, skin, and spleen. About 1,000 Europeans have LPLD, and it affects one in a million in the US – about 323 people. Prevalence is greater in Quebec due to a founder effect: French and Scottish settlers introduced two mutations three centuries ago. In the province 1 in about 6,000 people has the disease.

John Kastelein, Colin Ross, and Michael Hayden recall Glybera’s long developmental trajectory, which began in Hayden’s lab at the University of British Columbia, in a compelling article in Human Gene Therapy. In September 1986 they met a 19-year-old with sky-high triglycerides, painful pancreatitis, and skin lesions, and identified his LPLD mutation. A severely fat-restricted diet hadn’t helped.

A natural cat model and mice led to development of gene therapy for LPLD.

A natural cat model and mice led to development of gene therapy for LPLD.

Experiments using mice and cats followed, and eventually clinical trials tested several versions of a gene therapy delivered in adeno-associated virus. In severely affected patients, abdominal pain diminished, lipid levels fell, and they could eat more, including foods they couldn’t tolerate before. One patient even had a baby.

What would you pay to treat a painful and deadly disease?

Glybera costs so much because it is first-of-its-kind, was decades in development, and encountered an unusually thick regulatory morass. And the market is very small, so the monumental development costs must be divided by a small number of patients.

But Glybera is the test case for much wider application of the technology, which UniQure is exploring for several other indications. One is hemophilia B, the clotting disorder mentioned in the Talmud and seen in Queen Victoria and some of her descendants.

rbcs and clotHEMOPHILIA AND BLINDNESS GENE THERAPY WILL BE CHEAPER
Doing the math for hemophilia B, it’s easy to see how gene therapy will earn out its development cost. This is the less common form of the clotting disorder, affecting 4,000 people in the US.

Traditional treatment is the missing protein, clotting factor IX (FIX). It came first from blood donations, then using recombinant DNA techniques after HIV in the blood supply infected 90% of people with hemophilia in the 1980s.

Giving FIX protein to treat hemophilia B is expensive, painful, frequent, and not entirely effective. It costs $100,000 a year if used only to treat “bleeds,” and up to $250,000 if given 2 or 3 times a week to prevent bleeding. That’s about $20 million over a lifetime.

But giving the FIX gene — the instructions for cells to make the protein — could last forever and costs about $30,000. The lower price may be because the gene is small and simpler to insert into the viruses that carry out gene therapy than others, and a tiny jump in FIX level makes a huge difference in clotting time and how a patient feels. The promise of hemophilia B gene therapy is why several teams are racing to get it to the clinic. (Spark Therapeutics recently partnered with Pfizer to develop the gene therapy). I predict it will be among the first gene therapy approvals here.

My #1 prediction for first-to-be-approved gene therapy in the US is for Leber congenital amaurosis type 2 (LCA2), chronicled in my book The Forever Fix (shameless book plug in honor of pub date anniversary, today.) The treatment for this form of hereditary blindness won’t cost much, for several reasons: delivery into the eye is well-established, the inventors have forsaken earning anything, and kits are ready to ship to ophthalmologists.

Another intriguing new drug is Cerdelga™, to treat type 1 Gaucher disease. The FDA approved it in 2014.

Bone loses cells in Gaucher disease.

Bone loses cells in Gaucher disease.

GAUCHER DISEASE – FROM INFUSION TO PILL
Gaucher disease type 1 causes an enlarged liver and spleen, anemia, poor clotting, collapsed hips, arthritis, impaired lung function, bone pain and fractures. Cells become packed with lipids, and symptoms may begin at any time. It’s autosomal recessive, but carriers may develop a Parkinson-like condition later in life.

An earlier treatment for Gaucher, Ceredase, came on the market in 1991. Developed at Genzyme Corporation, Ceredase was an infusion and the first enzyme replacement therapy. In 1994. Cerezyme replaced it, made using recombinant DNA technology and altered to target fat-engorged Gaucher cells. Globally 5,000 people take Cerezyme, including 1,500 in the US.

Cerezyme works, but delivery isn’t easy. Dose and schedule of IV administration must suit each patient.

”For people receiving Cerezyme for a long time, that adds up to a lot of infusions and having to be poked every few weeks limits one’s schedule,” Gerald Cox, MD, PhD, Vice President of Clinical Development for Rare Diseases at Genzyme told me. A pharmacist must provide the drug and a nurse administer it, at home or at a clinic. “When we asked patients what more they would like from a treatment, they all wanted a pill,” Dr. Cox said.

(Genzyme)

(Genzyme)

So Genzyme researchers sought another way to intervene in the biochemistry – alleviate the buildup of substrate that occurs when an enzyme is blocked, as it is in Gaucher. FDA approved the substrate reducer Cerdelga – a capsule! – last year. Clinical trials were complicated, requiring patient volunteers to give up Cerezyme to test its new cousin.

The price per patient? $310,250 a year, a little more than its predecessor. Dr. Cox explains why.

“Orphan diseases follow a little different set of ground rules. There’s a lot of investment. But we have to go through all the regulatory hurdles that all the other companies do for common diseases, and when they want to recoup that investment there are 10 million people who are going to use the drug. You can keep the cost low because so many people are going to use it. But for an orphan disease with 5,000 worldwide, if you invest and divide by the number of patients, it winds up being a high price.” Relaxing regulations and shift of drug development towards academia might help for the ultrarare diseases, he adds, or foundations or governments stepping in, like for Kalydeco.

What would you pay to treat a painful and highly disruptive disease?

DOING THE MATH FOR USE IN THE US

Kalydeco for CF: 3,100 patients, ~$300,000/year each. For a 10-year-old who lives Logodollar2until 60, that’s about $15 million.
Glybera for LPLD: 323 patients, ~$1.4 million/lifetime
Cerdelga for Gaucher: 1,400 patients, ~$310,000/year each.

We’ve all heard the big pharma mantra, “R&D for a drug takes 10 to 15 years and more than $1 billion.” Add the costs of buying companies (like Sanofi bought Genzyme), and of discontinued clinical trials. Yet the treatments are justified when there isn’t anything else or existing approaches don’t work well or for everyone.

Now let’s look at hepatitis C.

Hepatitis C virus

Hepatitis C virus

THE HEP C CONUNDRUM
Hepatitis C is hardly a rare disease. About 2% to 3% of the global population has it – that’s  130 to 170 million people, including 3.2 million in the US. It’s more prevalent than HIV infection, and many people are unaware that they have it and can spread it. You’d think that’s enough people to keep costs down.

For more than two decades, treatment for hepatitis C infection has been the cytokine interferon and the antiviral ribavirin, which only some patients can take and which can make people pretty miserable. Availability of new drugs, based on the success of HIV antivirals, was good news indeed.

Last April, the World Health Organization called for assessing all infected people for two new drugs, because more treated people can block transmission.

An editorial in the New England Journal of Medicine was unusually optimistic: “Collectively, these regimens promise to transform hepatitis C from a condition requiring complex, unsatisfactory therapies and specialist care to one that can be effectively treated and easily managed by a general physician with few contraindications and side effects.”

But consider the price.

My friend Fred took the 3-month course of interferon/ribavirin/Solvadi. “My insurer paid. I paid only $20 for the whole course. That’s the good news. The bad news is that I relapsed after 90 days and am now on a newer combination drug, Harvoni. It’s reported to cost even more ($1,124) per tablet and I’ll need to take it for 6 months.” Solvadi is about $1,000 a pill.

Fred hopes he doesn’t get any surprise bills. “Keep your fingers crossed for me, this time I’m going to win!”’ Success rates for the new drugs are in the mid 90% range.

800px-HepC_replicationThe drug combinations are confusing. Harvoni is Solvadi plus a viral inhibitor called ledipasvir. Both combinations are from Gilead Sciences.

Olysio, at $733 a day, is from Janssen Pharmaceuticals and is taken with Solvadi, interferon, and ribavirin.

Viekira Pak, developed by AbbVie and approved last month, for about $925 a pill, combines three new antivirals and one old one. Like the hugely successful HIV drugs, these newcomers target various steps in the choreography of viral entry into human cells and replication.

Why do the hepatitis C drugs cost so much? A New York Times article lists a few justifications: R&D expenses, superiority to older treatments, future savings from preventing complications. True, the drugs seem to cure, compared to the HIV drugs that lighten viral load (unless hepatitis C virus peeks out in a few years). And Gilead paid $11 billion to the company that originated Sovaldi. But I don’t get it.

Prices in Pakistan, Egypt, China and India will reportedly be much lower. And by one estimate, cost to manufacture is actually about $150 to $250 per patient. A medical economist posited that it will take treating about 150,000 patients to recoup development costs.

What would you pay to stop a deadly disease? And how long would you wait?

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Adult Polyglucosan Body Disease (APBD): A Diagnostic Challenge

Globs of a carbohydrate called polyglucosan accumulate in astrocytes in APBD. (photo credit: Jensflorian)

Globs of a carbohydrate called polyglucosan accumulate in astrocytes in APBD. (photo credit: Jensflorian)

When Susan Coddon, a member of the board of directors of the Adult Polyglucosan Body Disease Research Foundation (APBDRF) e-mailed me a few weeks ago, I was intrigued. “Polyglucosan” didn’t ring any bells. Her husband learned he had the underrecognized condition in 2007, following a misdiagnosis of multiple sclerosis years earlier.

The APBDRF website describes a typical case: “In my early 50’s, I first experienced numbness in my hands, cramps, stiffness and heaviness in my legs. Also muscle twitching, soreness, foot drag and stumbling. Initially, I was incorrectly diagnosed with hereditary peripheral neuropathy. It took 13 years for a proper diagnosis.”

A recent article in the Jewish Daily Forward relates Hollywood photographer Robert Zuckerman’s multi-year diagnostic odyssey. That’s not unusual.

“Almost every patient we speak to goes on a 2 to 10 year search, in some cases even families of neurologists. We’re trying to get the word out, because APBD is very hard to distinguish from many other diseases,” Jeff Levenson, DMD, senior advisor to the APBDRF, told me.

Polyglucosan accumulates in astrocytes, a type of neuroglia. (Database Center for Life Science)

Polyglucosan accumulates in astrocytes, a type of neuroglia. (Database Center for Life Science)

APBD is inherited as an autosomal recessive trait, although many carriers have late-onset symptoms, making them “manifesting heterozygotes.” A genetic diagnosis may emerge from sequencing the exome, the protein-encoding part of the genome. Because APBD is actually an “atypical presentation” of a more familiar condition, tests for common neurological disorders are negative.

The particular problem of diagnosing APBD, however, may have more to do with its name than its DNA.

A COLLECTION OF COMMON SYMPTOMS

APBD begins, typically after age 35, with a numb foot that drags during walking. The hands too may exhibit this peripheral neuropathy, and the numbness may progress towards the body’s center. Fatigue sets in, and then urinary frequency and incontinence begin. There may be mild cognitive impairment.

Alarm bells may sound. Is it ALS? MS? Prostate cancer? Parkinson’s disease?

APBD is a leukodystrophy, a disorder of the white matter of the brain. This brain is from a toddler with an undiagnosed leukodystrophy. (Dr. Laughlin Dawes)

APBD is a leukodystrophy, a disorder of white matter. This brain is from a toddler with an undiagnosed leukodystrophy. (Dr. Laughlin Dawes)

Evaluation begins: blood tests, electromyograms, spinal taps, brain MRIs, which might show the telltale lack of white matter myelin of a leukodystrophy. But which one? Initial genetic tests come back normal, not surprising because the symptoms do not exactly match those of the more prevalent or better-studied inherited leukodystrophies.

If a health care provider strongly suspects an atypical case of a common condition, treatment may begin. Neurontin, prednisone, anti-seizure meds. Or perhaps more than one illness is at play – benign prostatic hyperplasia might explain the urination changes, a neuropathy the distal limb numbness.

Physical or occupational therapists can help a patient with activities of daily living while the docs try to figure out why the patient isn’t fitting into any categories. And why would an internist or even a neurologist trying to diagnose a tired and shuffling 50-something with urgency issues suspect a glycogen storage disease known for fatally disrupting the heart, nerves, and muscles of babies?

For that’s what APBD is: glycogen storage disease type IV. The unfamiliar “polyglucosan” intrigued me, so I got out my old textbooks to investigate the term, which sounds more like a sushi ingredient than a polysaccharide.

Glycogen

Glycogen

A CONFUSING NAME

Polyglucosan is a form of glycogen, which is a chain of glucose molecules. Glucose is the 6-carbon sugar whose chemical bonds provide the energy that cells use to manufacture ATP, the biological energy currency.

Glycogen normally branches at every 12 to 18 glucose units, and an enzyme – glycogen branching enzyme 1 (GBE1) – makes this happen. APBD arises from specific mutations in the gene that encodes GBE1 that allow some residual enzyme activity. Long unbroken chains of glycogen grow and glom and gum up the astrocytes that keep neurons functioning. Meanwhile, at the whole-body level, fatigue sets in as glucose becomes tied up. Mutations that lead to no enzyme activity are fatal in early childhood.

The “body’ in the disease’s name refers to the clumps of abnormal glycogen, not the person. Detecting polyglucosan requires special staining of a biopsy from a leg vein, finding deficiency of the enzyme in muscle samples or skin fibroblasts, and identifying mutations in the GBE1 gene in saliva.

Neither Lehninger’s Principles of Biochemistry, Morrison and Boyd’s Organic Chemistry, nor Bloom and Fawcett’s Histology, all circa 1975, mentioned polyglucosan or even glucosan. Googling “polyglucosan” led repeatedly back to APBD. Then I found “glucosan” at drugs.com, which referred to standard medical dictionaries that say “see glucan.”

Phaseolus_lunatus_flower_(5563988396)The dictionaries define “glucan” as any glucose polymer. But that would include starch and cellulose, which aren’t found in animals, as well as glycogen, which is.

The medical literature is confusing too. A 1980 paper in the journal Brain, from Salvatore DiMauro’s group at Columbia University, offers a murky definition: “A general term – polyglucosan body – is introduced to refer to these structures in all the circumstances in which they may occur,” which includes rare inherited conditions such as Lafora’s disease, movement disorders, glycogen storage disease type IV, diabetes, and normal aging. The abstract of a 2011 paper from the group in Human Molecular Genetics defines polyglucosan as “a poorly branched form of glycogen,” which seems rather vague. Finally, the title of a 2013 Annals of Neurology report helps: “Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease.

Given the terminology and the high prevalence of the individual symptoms, it isn’t surprising that APBD has a history of misdiagnoses, including Fabry diseaseALS, liver disease, and atypical Parkinsonism.

header-logoPerhaps the rhyming of three of the four letters of APBD, plus the fact that the term “polyglucosan” is broader and much less commonly used than “glycogen,” contributes to protracted diagnostic journeys. The condition may be fairly common, but often misidentified. In one study, among 380 Ashkenazi Jews the carrier rate was 1 in 34.5 — about the same as Tay-Sachs and other “Jewish genetic diseases.” But of course DNA doesn’t know the religious affiliation of the person in which it resides. Anyone can have APBD.

JScreen.org doesn’t yet list APBD but will do so soon, and it’s among the 14 glycogen storage disorder tests that Prevention Genetics offers. I wonder how common it is in other populations, and how often it is indeed shoehorned into other diagnostic codes, and patients receiving inappropriate treatments.

EMBRACING EXOME SEQUENCING

The APBD story offers a powerful example of the evolution of classifying disease by phenotype to the precision of classifying by genotype.

The polyglucosan disorders may remain an umbrella term, but within the grouping, APBD is distinct. For example, it’s different from a condition described in a 2013 Annals of Neurology report on a polyglucosan build-up that weakens muscles and affects the heart, but due to mutation in a different gene, RBCK1. (It encodes a ubiquitin ligase, part of the cell’s garbage disposal system.)

Panels of gene tests related by function are perhaps the dying embers of the “round-up-the-usual-suspects” approach to diagnose inherited disease. In contrast, exome sequencing can illuminate mutations in genes that clinicians might not have considered – like APBD being a glycogen storage disease.

Once exome sequencing becomes routine – say 5 years from now – a health care professional evaluating an adult with distal limb weakness, profound fatigue, and urinary urgency can pop a blood sample into a device that will quickly detect, or rule out, APBD – and other inherited conditions that it masquerades as. Meanwhile, APBD researchers are trying to get the word out about this illness that is still so easily confused with others.

I think all the ice buckets were used up on ALS, so I’m hoping that people with numb feet, fatigue, and urinary issues will mention the possibility of APBD to their health care providers.

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Why I Dislike “Best of” Lists and Eman Update from Liberia

icebergI’m not a big fan of end-of-the-year lists, such as the “top-10-scientific-achievements of the year” and the “top-10-genetics-stories-for-2014.” Science shouldn’t be a popularity contest. I wouldn’t suggest such a list for DNA Science, because:

1. I can’t possibly know about all research from 2014.

2. Others have created those lists.

3. I know how news is generated.

THE TIP OF THE ICEBERG
Those of us who read news releases daily – as science journalists do – didn’t need the recent study published in the British Medical Journal to confirm that these missives often hype research to ridiculous degrees. But it isn’t just exaggeration, headlines that suggest a study in mice is actually in humans, and use of vague terms such as “genetic engineering” that bother me about news releases.

My beef: news releases are a tiny sampling of what’s really happening in science.

256px-Bullhorn_font_awesome.svgResearchers with recognizable names, who publish in journals with high impact factors, and come from prestigious institutions with media machines and relentless PR firms, will be in the news releases that dictate what the public hears and reads. With aggregators rewriting news releases, with blogs linking to blogs linking to blogs, and the unending echoes of twitter and Facebook, we’re continually bombarded with variations of the same information. I’m guilty too.

Add to that chatter the fact that news releases precede online publication that precedes actual publication, it’s little wonder that by the time well-meaning friends send me news articles, it’s as Yogi Berra once said, “déjà vu all over again.” Thanks to writing this blog, now I’m getting pre-news releases!

And get this — there’s now a list of the top 10 science news releases!

Disclaimer: after having successfully avoided ever being on anyone’s “best of” compilation (blog, article, book, whatever), I today find myself quoted on a list of the stupidest startups, which of course links to a blog post.

Rather than writing about what the PR folk want me and everyone else to cover, I’m more interested in the experience of a lone parent who tells me about a child who has an unrecognized disease, or a study far down in the table of contents of an obscure journal, or a poster at a meeting from a post-doc or graduate student.

So DNA Science‘s subject list for 2014 doesn’t parallel the “top 10” lists. And it’s not that the entries on those lists aren’t great. For example, I haven’t gotten around to covering CRISPR (a method of genome editing) just yet – I’m simply overwhelmed with all there is to learn.

Because there’s no plan behind what I write about here, and it is year’s end, I checked. My math skills unfortunately do not extend beyond Facebook likes and Google Analytics.

DNA science covers more zebras than horses.

DNA science covers more zebras than horses.

RARE DISEASES AND WEIRD TECHNOLOGIES
If DNA Science has a focus, it’s rare diseases. Posts combine history, personal accounts, and recent research to tell about inherited immune deficiencies and  blindness, alkaptonuria, Wilson diseaseSan Filippo syndrome, and classic inborn errors of metabolism. DNA Science got an initially inexplicable 13,000 Facebook likes for a post on the rapid-aging disorder progeria, because by chance I hit “publish” just as an embargo broke. It happens.

Several posts went beyond the exome/genome sequencing that gets so much attention:

pink-150x150freezing employees eggs
using stem cells from fingernails
choosing whom to date based on DNA
transplanting turds
tissue engineering vaginas
manipulating mitochondria
probing polar bodies to select embryos

I did 3 or 4 posts each for stem cells, DNA sequencing (exome and genome), gene therapy, and genetic testing. Some posts made connections: when  inherited disease protects against infectious disease and the link between genetic testing and eugenics.

No Ice Buckets or Pink Ribbons for Rare Genetic Diseases said what many were thinking: the ice bucket challenge, although raising funds and awareness, was idiotic. DNA Science posts about ALS research from August 6 and April 3 got far fewer Facebook likes than the one in which I threw cold water on the topic. The intense focus on one disease was agonizing for some rare disease families, but some organizations capitalized on the fleeting attention.

1000 genomeFILM AND TV REVIEWS RULE
According to Google Analytics, far and away the top three posts were:

#1 Dan Brown’s Inferno: Good Plot, Bad Science

#2 How Ebola Kills

#3 Syfy’s Helix: Tired Plot, Bad Science, Fun

I cannot stress enough how badly Dan Brown’s novel Inferno (soon to be a film) and the TV series Helix butchered genetics. The Inferno post got 25,814 unique visitors, and Helix 13,785. Yet my post about the astonishingly accurate Call The Midwife episode about cystic fibrosis got only 2,395 (see the special on TV tonight). That’s famous novelist vs SyFy channel vs PBS. Maybe science is a popularity contest.

Sonn and grandson (4)EMAN IS WELL!
The #2 post, How Ebola Kills, was my #1, with other posts about my “son” from Liberia, Emmanuel Gokpolu.

I introduced Eman in the April 25, 2013 post on World Malaria Day. In contrast to the families with rare genetic diseases, Eman has struggled repeatedly with cholera, malaria, and other highly prevalent infectious diseases. That initial post got few hits. He appeared again, mostly in his own words, on October 23 this year in Eman’s e-mails from Liberia and Eman Reports From Ebola Ground Zero on November 6.

In July, when Eman’s emails became increasingly frantic with the initial burst of Ebola cases, I pitched his story to NPR, the New York Times, even my local newspaper. I was proposing to use his words, not mine, but my timing was off.

Editors here wouldn’t care about Ebola until a man came to the U.S. from Liberia and fell ill. I wouldn’t have guessed last July that Ebola Fighters would be Time magazine’s Person of the Year, but I’m glad the world outside Africa has finally woken up to the reality of our interconnected planet and the spread of infectious disease.

Eman and his family have survived, although his cerebral malaria came back mid-November. With medical school still on hold, Eman has become very involved with public health and the organization Determined Youth for Progress. He wrote on November 8, “our recent campaigns have targeted forgotten communities and elderly people. I believe an elderly person can easily influence his/her children and then their grandchildren. That’s easy in Africa. We had a tough time accessing some of these communities, but the commitment of our team won the day.

11/9: “I had the opportunity to address our President’s son, Mr. Robert A. Sirleaf, about Ebola on thanksgiving day in our community. It was great!! I also got a call from Action Contre La Famine(ACF) to serve as a Volunteer Health Promoter. I’m looking up to this new task. It might take me out of Monrovia to somewhere rural. Health authorities are on the alert for new cases in parts of rural Liberia. It’s no time to relax. We must build upon the gains we have made and strategize better to completely kick out Ebola.”

12/1: “We were able to renovate/construct sick wells in various communities, easing access to safe water for those communities. Our Ebola campaigns are going excellent and so far, no one has contracted the disease where we operate.

We have also decided to have a program for children on Christmas day. There are lots of things to be achieved if this program becomes a possibility. School is not opening just yet, so we have designed programs for the kids keeping in mind the presence of Ebola in our country.”

12/17: “I am in Bomi county, volunteering with ACF, about 2 hours drive from Monrovia. Despite the short distance, it is mostly remote. It was an epicenter at the height of the Ebola crisis, and it is still a hotspot for Ebola due to the fact that it is very close to Sierra Leone. We have been distributing preventive Ebola kits and encouraging people to report themselves as soon as they feel sick. It has been challenging.”

I’m so proud of Emmanuel, and grateful that he has survived the Ebola crisis.

plos_logoThis is my 112th post since DNA Science began on September 27, 2012. Thank you PLOS for the freedom to find my own examples of how genetics and genomics are increasingly affecting our lives. And thank you readers. Happy New Year!

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How to Use the Genetic Code for Passwords

 

Codons_aminoacids_tableNeed a password for a new device or service? Try the genetic code.

Messenger RNA triplets and the amino acids they specify provide nearly endless password possibilities. And it’s timely — the People’s Choice for Science magazine’s Breakthrough of the Year is “Giving Life a Bigger Genetic Alphabet.”

I began using the code for passwords years ago, when an IT-savvy friend setting up my clunky desktop computer told me a password should be:

• Alphanumeric
• More than 7 numbers or letters
• Obvious to me, but not to anyone else

The genetic code may seem like random gibberish to normal people, but can have meaning to biologists.

Francis Crick

Francis Crick

CRACKING THE CODE IN THE 1960s
The genetic code is the correspondence between the 20 types of amino acids and the 61 types of messenger RNA triplets (codons, representing DNA) that specify them. The same codons spell the same amino acids to all organisms. The RNAs of humans, hydras, hippos, hydrangeas, Haemophilus influenzae, and even viruses follow the same rules. This “universality” is why human proteins are manufactured in bacterial cells, bacterial insecticides are produced in corn, and an Ebola vaccine is made in tobacco cells.

Francis Crick proposed genetic code words (codons) as part of his “adaptor hypothesis,” which Marshall Nirenberg and Heinrich Matthaei at the NIH demonstrated with brilliant experiments in 1960 and 1961. They challenged bacterial cells to make tiny proteins using simple RNA molecules. When UUU… led to a string of phenylalanines, for example, they had the first piece to the puzzle. Fed more complex RNAs, the bacteria revealed more code words.

Marshall Nirenberg

Marshall Nirenberg

Wrote Dr. Nirenberg in his research notebook, “we would not have to get polynucleotide synthesis very far to break the coding problem … we could crack life’s code!” …“we would not have to get polynucleotide synthesis very far to break the coding problem … we could crack life’s code!” And so they did.

Crick, George Gamow, and other luminaries of the DNA discovery era famously formed the “RNA tie club,” in which each discoverer of a codon assignment was honored with a tie festooned with a double helix. The club had two dozen members, representing the 20 amino acids and 4 RNA bases.

Here are a few ways that combinations of codons and the standard three-letter amino acid abbreviations can make great passwords. (And a link to a list of amino acid abbreviations for those who don’t remember Bio 101.)

Data from the genetic code experiments.

Data from the genetic code experiments.

SUGGESTIONS

HISTORICAL
UUUpheAAAlysCCCpro (the first 3 pieces to the puzzle)
UUUAUApheilu (the first co-polymer in the experiments)

RANDOM
CUGleuAAUasnGUAval

PUNCTUATION
UAAUAGUGASTOP
AUGmetSTART

FASHION
Pink_UggsUGGtryptophan

CHEMISTRY
Sulfur-containing: AUAmetUGUcys
Rings: CCUproline   UAUtyrosine
Simplest: GGUglycine   GCAalanine   AGCserine

SYNONYMOUS (amino acids corresponding to more than one codon)
CUUCUCCUACUGleu   GCUGCCGCAGCGala

DISEASE-ASSOCIATED
Ehlers-Danlos syndrome: Arg134Cys
Huntington disease CAGglnx36HD
p53 oncogene UGAACAGUAp53
(Researchers should not use mutations they are working with. Someone will guess it.)

The genetic code is redundant — CCA and CCG both encode proline, for example – but passwords are not. Substitute the end G for the end A and your Amazon account won’t work.

gc posterPlan password choices, or have a chart of the genetic code in plain sight, as I do in my office. I got the poster after I had to change my Apple ID under time pressure, and I inadvertently typed in CAA for histidine, only to discover that I had specified glutamine.

Please send in other password suggestions!

Happy holidays and thanks for reading DNA Science!

 

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Sequencing Kids’ Exomes: More Good News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(NHGRI)

(NHGRI)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Exome sequencing could be done on newborn heelstick blood samples.

Exome sequencing could be done on newborn heelstick blood samples.

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

It’ll be like cord blood storage.

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

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

Thoughts?

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