“Saving Eliza” Campaign Helps Another Child

will in carValerie Byers had long suspected that her son Will’s diagnosis of autism was wrong. So when she saw a clip on the homepage of the Today Show about a little girl named Eliza, in late February, she knew instantly that 5-year-old Will had something far worse.

The clip featured the O’Neill family of Columbia, South Carolina. Last year, their “Saving Eliza” viral video raised awareness and funds to continue a gene therapy trial for their daughter’s inherited brain disorder, Sanfilippo syndrome type A.

The O’Neills have been under self-imposed isolation in their home for more than a year, even keeping 8-year-old Beckham from going to school and seeing his friends. They’re trying to protect 5-year-old Eliza from picking up a virus that could disqualify her from participating in a gene therapy clinical trial for the very rare disease at Nationwide Children’s. (DNA Science covered Eliza’s story here and here.)

logofinalWatching the Today Show clip, Valerie was transfixed. “Eliza resonated with me. Tears were falling down my face. As I saw Eliza’s story and the symptoms, I knew that’s what my son had,” Valerie told me on a recent afternoon when she managed to get her two kids to nap at the same time.

When she read the factsheet that Cara O’Neill, Eliza’s mom, who is a pediatrician, had put together, “my heart sank again. It just fit Will.”

Valerie and her husband Tim hadn’t really thought anything was seriously wrong with their “happy, healthy little boy. Then when he was 3 years old we noticed a slow down in his development. He was still hitting milestones, but slower. We were told to watch for the next year. By age 4 he had missed a couple of milestones in speech and motor skills. So from that point, last summer, 2014, he was sent to a pediatric specialist. They diagnosed him with autism,” she recalls.

But the diagnosis seemed off. Valerie knows kids with autism, and she has a master’s degree in psychology. But mostly she knows her son.

Will“Autism didn’t take into account everything that was different, quirky, about Will. And he was always social. He wanted to engage with people, he was just delayed in ways that didn’t make any sense. He had potty issues. His facial features correspond to Sanfilippo, a large head with prominent eyebrows and widely-spaced teeth. He has joint stiffness and trouble writing and pedaling. And he’s hyperactive.”

The distraught mother called the pediatrician right away, asking about the urine test mentioned in the factsheet. The next morning, she brought in a urine sample from Will.

A week later, Valerie and her husband Tim’s fears were confirmed. Will’s urine had the telltale buildup of heparan sulfate, a consequence of an impaired or deficient enzyme. A genetic test on a blood sample then confirmed that Will has mucopolysaccharidosis type IIIB. It’s a different form of Sanfilippo from Eliza’s type A, slightly less severe and rarer. But still a relentless neurodegeneration that would drastically shorten life.

Sanfilippo is a lysosomal storage disease, described in my first post about Eliza. Mutations in any of four genes cause it. Will, with type B, is 1 in 200,000. Incidence for all types of Sanfilippo is 1 in 70,000. Although all four types lead to buildup of the same biochemical – heparan sulfate – they require interventions targeted to the specific underlying genetic problem.

Valerie recalls learning the results of the genetic test. “It was a devastating day for us, to confirm that’s what was happening, to find out your child who is perfectly healthy and happy is now having his future taken away from him. It crushes you.”

Knowing helped. “We didn’t understand why there were things Will wasn’t getting, what we were doing wrong. Understanding what is really happening takes all that guilt away and you can focus on what’s important,” Valerie says.

But the family was lucky to get a diagnosis so quickly, because then an amazing thing happened.

“As we dove into the research and talked to the O’Neills and others we’ve connected with, we were able to get Will into a Sanfilippo syndrome type B clinical trial in Minnesota. He got the last spot! If we hadn’t seen Eliza’s story we wouldn’t have had Will diagnosed until next year, because he wouldn’t have regressed for another year,” Valerie says. The trial is testing an enzyme replacement therapy. Will, who turned 5 in June, was the eleventh and final patient.

The O'Neills (credit: Stacey Quattlebaum)

The O’Neills (credit: Stacey Quattlebaum)

“It was a pretty incredible set of circumstances,” says Glenn O’Neill. “We feel proud to know our supporters and awareness and early diagnosis forms helped this child get diagnosed and into a clinical trial, which could possibly save his life. If anyone asks about how can awareness help …. here you have a GREAT example!”

Will and Valerie travel from their home in Texas to Minnesota every other week, for an initial 24 weeks, after which Will will be eligible to continue for up to 3 years. So far, after three intravenous infusions, he’s doing well. And the parents are awaiting blood test results on their 20-month-old, Samantha, whose urine test was normal.

Now the Byers’ want to pay it forward, by talking about their experience and fundraising. “We don’t want other families struggling with this and deal with losing time. Not having a correct understanding isn’t fair to any family. Thanks to the awareness the O’Neills raised we now know and we can value our time.”

(Dept. of Energy)

(Dept. of Energy)

Genes may be silos in terms of therapeutics, which is why families funding research for subtypes of diseases must compete for media attention and funding. (See the comments to “When Celebrities Suddenly Care About Rare Diseases.”) A gene therapy for one form of Batten disease, for example, won’t help the other seven, caused by mutations in different genes. Hopefully, the 21st Century Cures Initiative, which recently passed in the House, will eventually lessen the competition. Meanwhile, Will’s story dramatically shows that raising awareness of any rare disease can help other families in unexpected ways.

For further information on Sanfilippo syndrome, see:

Cure Sanfilippo Foundation

Will’s facebook page WILLPowerMPS

Eliza’s facebook page

National MPS Society

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Hannah’s Hair – Why Traits Matter

Hannah 014It’s an unacknowledged law of nature that whatever the texture of a girl’s hair, she wants the opposite.

For years I wrapped my tangles around soup cans and around my head, squished it under irons, and subjected it to stinky straighteners. I’d often succeed, only to venture outside and have the hated curls spring anew.

Eleven-year-old Hannah Sames also relaxes her curls. In fact, the pale kinks were the first thing Hannah’s parents, Lori and Matt, noticed when she was born. “Their other daughters, Madison, five, and Reagan, two, had stick-straight hair, as do Lori and Matt. When the birthing goop had dried, Hannah’s curls were odder still, weirdly dull, like the ‘before’ photograph in an ad for a hair conditioner,” I wrote in my gene therapy book. A more recent story about a little girl with curly hair but straight-haired siblings and parents in the Times of India is remarkably similar.

Hannah 019The photo to the right of Hannah and her dog Ginger is on the cover of my human genetics textbook, to show a striking variant of an inherited trait, hair texture. My best friend Wendy Josephs took that photo and others in this post on an early spring day in 2011, when we visited Hannah and her sisters. Those photos were the last taken before Hannah began the quest to straighten her hair. It turns out that the unusual kinky hair is an important clue to identifying a very rare neurological disease.

Hannah has giant axonal neuropathy – GAN. It’s like amyotrophic lateral sclerosis (Lou Gehrig’s disease) in a child, a gradual failure of motor neurons to stimulate muscles and eventually failure of sensory neurons too. Swollen intermediate filaments (IFs) stuff the axons in what one researcher terms a “logjam.” Whole-body effects are slow yet profound, and ultimately overwhelming. I’ve covered Hannah’s story here, beginning with “A Little Girl With Giant Axons, A Deranged Cytoskeleton, and Gene Therapy,” and most recently the wonderful news that a gene therapy clinical trial is finally underway.

family hannah looking backwardThanks largely to the herculean efforts of the Sames family, the first child received an infusion of working gigaxonin genes into her spinal cord at the NIH Clinical Center on May 27. But it isn’t Hannah. She can’t participate until the researchers figure out a way to dampen a potential immune response. Hannah’s two mutations are full deletions, and so if the missing protein suddenly shows up, her immune system could go into overdrive.

An important clue in Hannah’s diagnostic odyssey wasn’t a genetic test, an exome or genome sequence, or a scan. It was her hair. Hannah’s aunt showed a video of her niece to a friend who worked with children who have muscular dystrophy. The friend urged the family to take Hannah to a pediatric neurologist, and when they did, he stared at her hair and went to his bookshelf. “He took out a huge textbook and showed us a photo of a skinny little boy with kinky hair, a high forehead, and braces that went just below the knee – he looked exactly like Hannah. And he had GAN,” Lori said.

Lori and Hannah Sames (Dr. Wendy Josephs)

Lori and Hannah Sames (Dr. Wendy Josephs)

In 1971, researchers at the University of California, San Francisco discovered the giant axons and named the disease, noting the extreme curls. Their subject was a six-year-old girl whose neurological decline was just like Hannah’s.

In 1974, another case appeared in the medical literature. Those researchers urged doctors to suspect GAN “in a patient with tightly curly, pale scalp hair, unlike that of his parents.”

By 1987, only twenty more cases had been reported. The numbers grew, slowly, until by 2000 enough cases were known to finally search for mutations in common. That led to chromosome 16 and the gene that encodes the protein gigaxonin, which regulates the degradation of IFs in a variety of cell types. Part of the cytoskeleton, IFs are actually more abundant than the microtubules and microfilaments that get all the attention in textbooks. In GAN, missing or abnormal gigaxonin most obviously disrupts the neurons’ IFs — aka neurofilaments — but also alters how keratin IFs form in hair.

GAN, like many single-gene diseases, is “pleiotropic” – it has several signs and symptoms. When patients present with different subsets of the manifestations, a single disease can appear to be several. One version of cystic fibrosis, for example, causes only male infertility; another causes only sinusitis and bronchitis. So some kids with GAN don’t have the kinky hair. But for many, the trait is very helpful in distinguishing GAN from Charcot-Marie-Tooth disease and other “polyneuropathies.”

The bigger picture of Hannah’s hair is that we shouldn’t lose sight of the value of clinical descriptions, whether it’s something as obvious as a little girl’s curls, or a quirk that an astute parent reports to a physician. The value of a clinician assembling diagnostic puzzle pieces and then pulling down a dusty textbook from a shelf and pointing to the likely diagnosis might change to googling, but it mustn’t vanish as we come to rely more and more on DNA sequences to help us put names on collections of symptoms.

As I mentioned in last week’s post, I fear we are entering a “forest for the trees” situation with the ever-increasing pace of exome and genome sequencing. This week’s bigger-and-better genome news comes from an article in PLOS Biology“Big Data: Astronomical or Genomical?”

(Jane Ades, NHGRI)

(Jane Ades, NHGRI)

Zachary Stephens of the University of Illinois, Urbana-Champaign and colleagues compare the data spewing from human genome sequencing to that from Twitter, YouTube, and astronomy. With data from human genome analysis doubling every 7 months and a billion fully sequenced human genomes projected within a decade, co-author Mike Schatz of Cold Spring Harbor Laboratory says, “People may have to start using the term ‘genomical’ to indicate the hugeness that ‘astronomical’ currently signifies!”

I’m all for the new term, genomical, for many reasons, not the least of which is that maybe I’ll finally stop getting blank stares when I tell people what I write about. And sequencing is dramatically ending the diagnostic odysseys that were once the norm for rare disease families. But at the same time, practitioners will always need to carefully examine their patients and listen to them and their family members. For in some cases, especially of a rare condition, a characteristic as seemingly innocuous as pale, kinky hair can be as helpful as a sequenced genome

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Aicardi Syndrome: Genome Sequencing Illuminates Another Rare Disease

Polymicrogyria_arrowsAs my inbox fills with ever more updates on the number of human genomes sequenced and the plummeting time and cost of next next next generation sequencing, I find myself hitting delete more and more often. Instead, I’m drawn to the small stories, the incremental revelations that may affect only a few individuals.

A few weeks ago, a study published in Investigative Ophthalmology and Visual Science caught my attention. Researchers at the  Translational Genomics Research Institute (TGen) in Phoenix used exome and genome sequencing to probe the origins of a condition I’d never heard of — and the findings were surprising.

Aicardi Syndrome is a neurodevelopmental disorder of childhood. The three cardinal symptoms are:
• “infantile spasms.” These may begin before birth and after progress to seizures
• lack of the corpus callosum, the band of nerve fibers that joins the right and left brain hemispheres
• “chorioretinal lacunae,” which look like white craters in photos of the retina

All affected children have the eye abnormality, but only some have brain manifestations. Brain imaging reveals a constellation of abnormalities, including convolutions that are too thick or too thin, cysts, enlarged spaces (ventricles), and a general asymmetry. Children tend to be developmentally delayed and intellectually disabled, with small hands, scoliosis, gastrointestinal problems, and unusual facial features.

(Jonathan Bailey, NHGRI)

(Jonathan Bailey, NHGRI)

French neurologist Jean Aicardi first described the syndrome in 1965. Only about 4,000 children worldwide are known to have it, about 900 in the U.S. Nearly all are girls; a few reports describe affected boys with XXY (Klinefelter) syndrome. They have an extra X chromosome.

The most likely explanation for the origin of Aicardi syndrome, based on whom it affects, is a dominant mutation in a gene on the X chromosome. In this rare mode of inheritance boys, lacking a second X, are much more severely affected than girls. If boys survive to be born, they may have symptoms so much more severe than those in girls that they are perhaps not even recognized as having the same syndrome.

X-linked dominant conditions are exceedingly rare, because a male can’t pass it on (he’d be dead) and a female would likely be too impaired to have kids. So cases reflect a mutation that arises anew, or “de novo.” The condition is genetic, but not inherited.

The TGen researchers were intrigued by reports of two boys who have normal XY male chromosomes. Might a gene not on the X cause Aicardi syndrome? The role of the X had been inferred from the preponderance of girls, not from identifying a specific responsible gene. So the investigators sequenced ten child-parent trios in search of candidate genes. Perhaps a gene on an autosome affects expression of genes on the X.

Hippopotamus_amphibius_-_Homosassa_Springs_Wildlife_State_Park,_Florida_-_2010-01-13One child had a de novo mutation in a gene called TEAD1. That stands for the Tea domain, which is part of the Hippo signal transduction pathway. TEAD1 enhances the expression of several genes involved in the cell cycle and apoptosis. And it’s highly expressed in the hippocampus (no link between the two hippos and the fact that it is my favorite mammal).

Further experiments showed that TEAD1 fit the bill as a candidate gene for at least some cases of Aicardi syndrome, even though it’s not in databases commonly used to match mutations to phenotypes. But it is associated with an eye condition, Sveinsson’s chorioretinal atrophy. Exome and genome sequencing are enabling us to connect conditions that we didn’t know were connected.

The biggest surprise was that TEAD1 isn’t on the X chromosome; it’s on chromosome 11. And that has implications for diagnosis, which is based on clinical exam, brain imaging, and ophthalmological evidence. A handful of genetic tests are used to rule out Dandy Walker syndrome, agenesis of the corpus callosum, neuronal migrating disorders, and a few others.

Summarizes co-author Matt Huentelman, PhD, head of the Neurobehavioral Research Unit at TGen:

“Our finding suggests that the field may need to revisit how this disease is diagnosed/phenotyped. Perhaps there are male patients out there with the ‘wrong’ label or no label at all for their disorder simply because they weren’t the ‘correct’ sex to receive the diagnosis of Aicardi. Or Aicardi could look similar yet different in male patients. The other big take home message for me was that for a disease that is thought to be an ‘easy’ one to phenotype/diagnose… we saw a wide range of phenotypic characteristics and currently no overlapping genetics.”

dnaFinding a candidate gene is a giant step forward. Not only may it refine diagnosis, but understanding the function of that gene may reveal the mechanism of the pathology — at least for some cases. And that can inspire drug discovery and perhaps other therapeutic approaches like gene or cell therapies, or even identify drugs for repurposing.

See the Aicardi Syndrome Foundation for information on genetic research at the Baylor College of Medicine and the University of California, San Francisco, and the Facebook group.

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When Celebrities Suddenly Care About Rare Diseases

3 kingsI have followed, in awe, the tireless efforts of families that have rare genetic diseases to raise awareness and funds.

Bake sales and bike races, balls and raffles, exhausting and all-consuming. But these efforts pale when a performer or other famous rich person suddenly and explosively steps up to support such a disease, solely because someone they know has just been diagnosed. As if dozens of families haven’t already been trying to fund clinical trials for years. Last summer’s “ice bucket challenge” was the epitome of the power of viral social media, with the message about ALS lost in the excitement.

When celebrities suddenly care about rare diseases, I wonder what my friends in the rare disease community think. They’re happy, of course, at the attention, yet perhaps a bit unglued by the power of the famous – but maybe afraid to say so.

That happened recently for Batten disease, a devastating group of brain disorders that strike in childhood. And one family isn’t afraid to speak out.

A hippo, Laura, and Taylor

A hippo, Laura, and Taylor

Two years ago and one year ago, DNA Science heard from Laura King Edwards, who has been running races in all 50 states in honor of her 16-year-old sister Taylor, who has Batten disease. This week, DNA Science borrows the blog posts of Laura and her mother Sharon King, responding to last week’s avalanche of concern for the disease that is taking Taylor away. Laura blogs at Write the Happy Ending and Sharon at Taylor’s Tale.

LAURA KING EDWARDS: #CureBatten Forever

Celebrities like Mark Wahlberg, Jennifer Garner and Megan Fox are rallying to save the lives of two young girls diagnosed with a rare form of Batten disease. The girls, Charlotte and Gwenyth Gray, are the daughters of Hollywood producer Gordon Gray. Gray is known for movies like “The Rookie,” “Miracle” and “Million Dollar Arm.”

Now he’s trying to raise $10 million to save his kids.

Batten disease has never been so squarely in the public eye. The Grays have A-list connections, and those connections have helped land the family’s story on CNN Health, Cosmopolitan, Good Morning America, People, Time, The Today Show, US Weekly and many others.

Did I mention all of that happened in 24 hours?

Taylor King.

Taylor King

On July 24, my family will have been fighting Batten disease for nine long years. I’m proud of what Taylor’s Tale has accomplished in that time.

We’ve been a top funder worldwide for infantile Batten disease research, and nearly every dollar has been donated by an individual touched by our story. We’ve effectively increased awareness of Batten disease within and outside Charlotte. We’ve become rare disease advocates and played an important role in rare disease legislation, including a new bill in North Carolina that we initiated and which passed unanimously in the N.C. House this spring.

In those nine long years, Batten disease has stolen almost everything from my little sister. Everything, that is, but her courage.

Like my mom, it is difficult for me to feel excited about the Grays’ story. I knew and loved Taylor when she was healthy, and so it’s easy for me to see my sister in the Grays’ video that shows the girls laughing and smiling and playing. I read all I needed to know about the symptoms of Batten disease online in the moments after my mother called to inform me of Taylor’s diagnosis. But those words never really sank in until they became our reality – until we were forced to live them.

Laura and Taylor

Laura and Taylor

Every new diagnosis is a tragedy, regardless of how much awareness or money it brings. I hate this disease with every fiber in my body and I hate watching it shatter the worlds of new families, as it shattered ours.

The Grays can’t do anything about the fact that Batten disease is in their genes. What they can do is FIGHT it. What they can do is believe. I admire them for doing exactly that.

Charlotte and Gwenyth have an extremely rare form of Batten disease, CLN6, that affects fewer than 10 kids in the world. It is a variant form of late infantile Batten disease (CLN stands for “neuronal ceroid lipofuscinosis.”) Batten as a whole affects thousands. The diseases are genetically distinct. Infantile Batten disease – Taylor’s form – is CLN1.

While the efforts of the Charlotte and Gwenyth Gray Foundation to cure CLN6 will certainly help all of us indirectly, we still need to find treatments for ALL forms of Batten disease and save thousands of children worldwide – the children of today and the future Charlottes, Gwenyths and Taylors.

If the Grays raise their $10 million, it won’t save the rest of us. Even if things are learned that can move the science forward for other forms, it won’t pay for that work. What they may do is prove that answers are possible, if funding exists.

My challenge to you, if you’ve been touched by Taylor’s story or the story of Charlotte and Gwenyth Gray, is to stick with the Batten community. Regardless of how long celebrities continue to tweet photos and pleas for $1 donations, we’ll need you for the road ahead, and the science still has to work.

My heart goes out to the Grays and their girls. I’ll be pulling for them!


A question mark popped up in my inbox this morning, a friend wondering why neither Taylor’s Tale nor a member of Taylor’s family had responded to the recent release of a website and video from the family of Charlotte and Gwenyth Gray, two young sisters recently diagnosed with CLN6, a form of Batten Disease. The story flooded my Facebook feed yesterday.

Here’s the easy answer: I’m still “processing it.”

I cried watching the video. Change the faces, and it could be my family. The beautiful children, shock, fear…hope. It’s life repeating itself. It’s something that’s happened too many times since Taylor’s diagnosis.

Taylor eating a brownieWhat makes the Gray family’s story different is that they have “connections” that can make a huge difference in raising awareness and the all-important funding to get to hope. We’ve been working for nine long years, spreading the word and providing whatever funding we could raise to propel research forward. I daresay the Grays will long surpass us in nine short days.

How often have many of us in the Batten community thought, “If we could capture the media’s attention in a big way, we could move even more quickly to find treatments…and one day, a cure?” Now, one family’s high-profile celebrity connections have garnered valuable media attention.

But there is no joy in having the Grays join our ranks. Their story has ignited awareness of Batten disease…but at what cost? I would rather the girls be healthy. As grateful as I am for what they and their friends are doing, my heart hurts because another family…more precious children…are battling the monster that is Batten disease. And that reality is not easy to process.

Kudos to the Grays and the many other brave families we’ve met along the way for taking a stand – for their unwillingness to accept “no cure.” We took that stand the day Taylor was diagnosed with Batten disease, and we’ve never backed down. We still believe. Working together, we WILL win this fight.

Staying power is important. As a community, how can we capture this momentum for the long haul, and for all of the kids suffering from the various forms of Batten disease? How can we make this story matter to the world tomorrow? The challenge now will be for the Charlotte and Gwenyth Gray Foundation, Taylor’s Tale, and ALL organizations fighting Batten disease and other rare disorders to:

young Taylor• Capitalize on the awareness created by Charlotte and Gwenyth’s story

• Transform new donors into repeat donors, advocates and storytellers for the cause

• Support the work funded by the influx of new donations to ensure it translates into a treatment

$10 million is an enormous amount of money, and the work will certainly inform progress in other forms of the disease. Therein lies our tagline, “A victory for one is a victory for all.”

Ten million dollars won’t be enough, however, to reach clinical trials for all forms of Batten disease. Taylor’s Tale and other related groups will continue to need additional funding and your support to build a better future for children like the Grays’ girls, Taylor and so many others.

(Taylor’s Tale is funding gene therapy research for infantile Batten disease at the Gene Therapy Center at the University of North Carolina. Thanks to Laura for sharing the family’s photos.)

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“Genes in Space” Student Finalists Announced

Lost_in_Space_Jonathan_Harris_&_Robot_1967I thought for sure some of us would be living on the moon, or beyond, by now. In the late 1960s, it was easy for a kid to believe that.

For many families back then, a launch was a special time to gather around the TV to watch the take-off and splashdown. I remember the low points and high points. The launch pad accident of Apollo 1 on January 27, 1967, when 3 astronauts died. When we lost contact for a short time with the crew of Apollo 8 as they rounded the dark side of the moon, Christmastime 1968. And of course I watched, from summer camp, in July 1969 when Neil Armstrong, of Apollo 11, took his famous one giant step onto the lunar surface.

Meanwhile, TV fed the space fever of scientists-to-be. From 1965 to 1968, Lost in Space chronicled the adventures of the Robinson family and their crew and lovable robot, derailed from their destination to the third planet in the Alpha Centauri star system thanks to stowaway Dr. Smith. It was silly, a little like Gilligan’s Island goes celestial. But with Apollo flights blasting up at regular intervals, it didn’t seem all that impossible.

640px-Leonard_Nimoy_William_Shatner_Star_Trek_1968Offset by a year, from 1966 to 1969, was the original Star Trek, which needs no description. 1968 was also the year of 2001: A Space Odyssey.

Star Trek reruns sustained me through college in the 1970s, and then in 1977, grad school, came Star Wars. My brain re-emerged from the fog of young motherhood to the The X-Files from 1993 to 2002. And now I can’t wait for the film version of The Martian. The book, by Andy Weir, is amazing.

Because of the importance of space exploration in sharpening my own scientific senses, I was thrilled to learn about the first Genes in Space competition, sponsored by Boeing, the Center for the Advancement of Science in Space, Math for America, and miniPCR.

Hundreds of students in grades 7 to 12 sent in their ideas for experiments that use DNA analysis to solve a real-life space exploration problem. After researchers from MIT and Harvard help the five finalist teams prepare their experiments for space travel, the students will present their proposals at the International Space Station (ISS) Research and Development Conference in Boston, Massachusetts, July 7-9, and the winner will be announced. The winner(s) will watch the launch that will take their idea 250 miles above the Earth, to come to life aboard the ISS.

Here are the five finalists, with information from their terrific proposals. Congratulations!


shuttleworthJaclyn Shuttleworth, Jon Hamilton, and Sarah Golden, future doctors from Braintree, MA, are interested in the effects of radiation exposure on health. Astronauts going to Mars and beyond may face this problem, despite protection by the Van Allen belts. The students will assess double-strand DNA breaks in plasmid DNA before and after the exposure, and place samples in different locations on the ISS.

“Using this simple system, we hope to identify structures and parts of the ISS that already offer some passive shielding from this radiation, as well as parts of the station that increases risks through secondary radiation from the interaction between the station and the radiation. This information may then guide the design or use of future deep-space vehicles,” they wrote.

Anna-Sophia Boguraev, of Bedford, NY, plans to assess effects of microgravity and cosmic radiation aboard the ISS on the methylation patterns that alter cytokine gene expression in T cells. Identifying such epigenetic changes could “provide a potential therapeutic target for improving immune system function in astronauts,” she wrote.

The protocol will parse the effects of exposure to microgravity and radiation, and explore the interaction. The approach “will also help understand how to modify the logistics of future flights to better protect astronauts and eventually, as epigenetics drives embryonic development, their children, both on earth and in space.”

Anna-Sophia wants to study biochemistry. She began with a science fair project in elementary school, when she extracted DNA from vegetables using a blender.

Tarun Srinivasan, of Houston, TX, plans to examine effects on the gut microbiome of spending time on the ISS. Do microbiome changes against the backdrop of waning immunity in space increase susceptibility to bacterial infection? Because microbiome changes underlie or accompany many diseases, “this study is relevant in that it addresses the health of the individuals who venture into the final frontier,” Tarun wrote.

Tarun has developed a schedule to frequently collect stool samples from the astronauts before departure, during space travel, and after. Analysis will consider age, gender, medication usage, alcohol consumption, diet, and exercise as well as the taxonomic profiles of gut microbiome residents.


“Since the beginning of time humanity has been asking ‘are we alone?’ If life is found elsewhere it would affect all of humanity. Because it is unknown what may be encountered, it is crucial that all nucleotide bases that are available be examined,” wrote Alyssa Huff of State College, PA.

Alyssa’s experiment will test the ability of miniPCR to identify “unnatural base pairs” in the genetic code of organisms or viruses that the ISS may encounter. “The DNA or RNA of extraterrestrial life may have different nucleotides then the DNA/RNA of Earth’s life,” she wrote. Her experiment will test whether miniPCR can amplify such different DNA as well as reverse transcribe RNA into cDNA.

AnimaPiolinmarcianocolor(The experiment assumes that a nucleic acid is the basis of the instructions for life beyond Earth. I’m reminded of the silicon-based Horta detected on Janus VI on the original Star Trek. However, the Horta and her eggs will not be detected until 2267.)

Alyssa hypothesizes that biochemical traces of life will most likely come from the moons of Jupiter and Saturn, consistent with 2001: A Space Odyssey.


chang+bandieraJonathan Change and Thiago Bandeira, of Sammamish, WA, are fascinated by OU-20 bacteria, microbial residents of cliffs from an English fishing village that famously survived on the outside of the ISS for 553 days.

Does genetic change enable these bacteria to survive exposure to cosmic radiation? The students plan to subject several species of bacteria to space conditions and then analyze shared genes using PCR and sequencing.

Congratulations to all teams who entered the competition– you are all winners!

UPDATE: Congrats to Anna-Sophia Boguraev, the winner!

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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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