Targeting Cancer: A Basketful of Hope

basketTargeted treatments for cancer have been extending and saving lives for more than 15 years — precision medicine isn’t a new idea in oncology. Now drugs pioneered on select, specific cancers are, one by one, finding new applications.

The first wave of targeted drug approvals were for cancers associated with specific mutations. Herceptin (traztuzumab) led the way, approved in 1998. It’s a monoclonal antibody deployed against the HER2/neu receptor that is overabundant in some aggressive and early-onset breast cancers. Robert Bazell’s excellent book Her 2 tells the tale.

In 2001 came the blockbuster Gleevec (imatinib), a small molecule tyrosine kinase inhibitor that intercepts signals to divide. Erin Zammett’s My So-Called Normal Life with Cancer relates that story. A very young editor at Glamour magazine when a routine check-up revealed chronic myelogenous leukemia, Erin’s recovery was one of the first of thousands thanks to this now famous drug.

In 2004 came the monoclonal antibody Avastin (bevacizumab), targeting vascular endothelial growth factor A to squelch the torturous blood supply feeding certain colon tumors. In 2011 Zelboraf (vemurafenib), a serine/threonine kinase inhibitor, entered the market. It blocks signals for melanoma cells to divide in people who have a specific mutation in the BRAF gene called V600. These are just a few.

(Jonathan Bailey, NHGRI)

(Jonathan Bailey, NHGRI)

The second wave of targeted cancer treatments began when the trailblazers became available for other cancers. Gleevec is now used for several blood and bone marrow cancers; Herceptin for tumors of the stomach and junction between the esophagus and stomach; and Avastin for types of lung, kidney, ovarian, and brain cancer. A study published two weeks ago in The New England Journal of Medicine reports use of Zelboraf (vemurafenib) for cancers besides melanoma, some quite rare.

The third wave of precision cancer medicines will combine targeted and other therapies. The National Cancer Institute’s Molecular Analysis for Therapy Choice (MATCH) trial will assign patients with lymphomas or solid tumors at 2,400 study sites to receive any of 20 drugs, including combinations, matched to 143 tumor mutations. Much of this matching of medicines to tumors is possible because of The Cancer Genome Atlas (TCGA), an NCI/NHGRI effort to establish mutational landscapes for the more than 200 types of cancer. In 2012, the Pan-Cancer Initiative continued TCGA to systematically explore relationships among tumor locations in the body and mutations.

The recent report on expanding use of the melanoma drug illustrates the insights that arise from these types of investigations. It is an ongoing “basket study” that bundles patients with cancers with targetable mutations that are too rare to fit ongoing clinical trial protocols. The figurative basket includes several types of traditionally-defined cancers. Edward McKenna, Senior Medical Science Director at Genentech, the manufacturer of the melanoma drug, explains. “Mutations targeted by medicines already approved or in development for specific cancers may be present in a broad range of cancers. Often these mutations are only present in a small subset of any specific tumor type. It is not practical or possible to study every medicine and target in every tumor type. Grouping diverse tumors into basket studies allows us to efficiently study them and pursue further evaluation of any promising activity.”

The NEJM study looked at BRAF V600 mutations in colorectal cancer, non–small-cell lung cancer (NSCLC), and the much rarer Erdheim–Chester disease, Langerhans’-cell histiocytosis, cholangiocarcinoma, anaplastic thyroid cancer, and multiple myeloma, as well as a few “orphan” cancers. From 2012 to 2014 the 122 patients from 23 centers worldwide took the pill twice daily.

Q and A

José Baselga, MD, PhD, (Memorial Sloan Kettering Cancer Center)

José Baselga, MD, PhD, (Memorial Sloan Kettering Cancer Center)

José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center and lead author on the recent NEJM paper, was kind enough to speak with me about the exciting study results.

RL: NBC Nightly News on August 19, when the study was published, showcased a 59-year-old jazz pianist diagnosed with glioblastoma two years previously, whose tumors had vanished following treatment with vemurafenib. Can you describe another notable recovery among the participants?

JB: Yes, The other situation in which treatment with the drug will probably be implemented very soon is Erdheim-Chester disease (a rare form of non-Langerhans cell histiocytosis, it is an adult-onset cancer of tissue macrophages that causes organ failure and bone pain). 50% of patients have the BRAF mutation. This disease has no therapy whatsoever. The first patient we treated had a huge response. She had been on the way to hospice. She couldn’t walk. Two weeks after joining the clinical trial she came back, walking and feeling fine. It’s been over a year since treatment and she is absolutely asymptomatic. We had patients from all over the place coming to be treated on this protocol and every one had tumor shrinkage. None progressed. It was remarkable.

Another great example is non-small cell lung cancer, not only because of the high response rate but because in lung cancer it is common practice to test for EGFR and KRAS mutations, so BRAF should be part of the panel. (Eight of 19 patients with NSCLC had partial responses, median progression-free survival was 7.3 months and is ongoing, and preliminary 12-month overall survival was 66%.)

RL: It must be difficult to recruit volunteers who haven’t been treated, yet that is the optimal way to evaluate a candidate drug. In the study, 89% of the patients had already been treated for their cancers. Will future targeted treatments be given earlier in the clinical trial process?

JB: Patients typically presented at stage 4 and they’d received whatever therapy is approved for their type of cancer, and at that time patients were checked for mutations. I think that as we move on, we will be doing genomic testing up front at the time of diagnosis, and these treatments can become frontline.

RL: David J. Hunter from the Harvard T. H. Chan School of Public Health and Ralph D’Agostino, Sr, from Boston University write in an accompanying Perspective that “the response to a specific mutation is likely to depend on the anatomical site of origin” and that predictions based on mutations “are overstated.” What is the relationship between diagnosis based on location (“conventional tumor nosology”) and diagnosis based on mutation (“molecular nosology”)? Are they both important?

Cancer is a choreography of mutational steps. (Darryl Leja, NHGRI)

Cancer is a choreography of mutational steps. (Darryl Leja, NHGRI)

JB: The pendulum has swung. When we began to do studies with gene mutations, testing for the genes we knew and thought were the drivers, there was a school of thought that perhaps the genes and not the tissue of origin would dictate the behavior of the tumor and what therapy would need to be offered to these patients. So people were saying instead of having a breast clinic we’d have a BRAF clinic and a KRAS clinic and a HER2 clinic and so forth. What we’ve learned is that the driver mutation matters, but the tissue of origin is also important. You cannot ignore one or the other; you have to take them together.

RL: Were any of the study results surprising?

JB: Yes, for colon cancer. BRAF colon cancer has a very poor prognosis and median survival of 3 months. We began to treat patients with a single agent (vemurafenib) and had 0% response, not a single patient responded. We were about to close the study and call it a day when two papers were published, one in Nature and one in Cancer Discovery, that said that blocking BRAF activates the EGF receptor. The way to treat these colorectal cancers, then, is to use both a BRAF inhibitor and an EGFR inhibitor. We modified the protocol, adding the EGF receptor antibody cetuximab, and BAM! We saw a tremendous number of responses. We learned that in colon cancer when you block BRAF you also have to block the EGF receptor. This doesn’t happen in lung cancer and in Erdheim–Chester disease.

So before targeted prescribing gets easy it’s going to get complicated, because the tissue-of-origin matters and we will have to deal with both that and the mutation. So our dream of the BRAF clinic goes out the window, and whatever replaces that dream will be complex. These results point to the importance of cell lineage.

RL: TV ads abound for personalized cancer treatment centers, with soothing words and warm fuzzy images. Are such genome-based initial treatments for cancer as available and accessible as these pitches project?

JB: Precision medicine is a buzzword and it has lost some of its value by overuse. Today we have a precision medicine capacity to sequence the genomes of tumors and identify some mutations and based on that information, we might be able to propose tailored treatment. In my opinion that only happens in academic institutions that have research background with serious sequencing efforts.

I think we should stick to the facts. When people announce precision medicine on TV, that’s wrong. I’d never do it. We need to take it seriously and be humble and take a step-by-step approach. At Memorial we are conducting 25 to 30 basket trials, and we offer them to the patients. But this is a work-in-progress. We have a duty to not oversell this to the public.

Testing tumor DNA in the bloodstream is replacing biopsies for some cancers. (Jonathan Bailey, NHGRI)

Testing tumor DNA in the bloodstream is replacing biopsies for some cancers. (Jonathan Bailey, NHGRI)

RL: Where do you see cancer treatment options 10 years from now?

JB: We are going to be able to look at mutations in the blood in a way that will be easy, fast, cheap, and reproducible. We will not only know the mutations, but also how the tumor is evolving to those mutations and the mechanisms for resistance to therapy. We cannot biopsy a tumor every 2 weeks or even months, but we can check the blood as much as we like. That will enable us to use a perfect combination of therapies.

But I don’t think we will cure many patients with just with one therapy. Every tumor has a repertoire of pathways and responses to survive. That repertoire is finite. It has an end. There won’t be a single therapy, so we must be able to combine therapies and identify responses. Then, when things get messy, with multiple mutations far beyond any we could treat, we’ll have the power of immunotherapy. Signatures of genomic alterations predict benefits to some immunotherapies. That is, if a tumor acquires more mutations, there’s a higher likelihood that immunotherapies will identify a tumor as foreign.

Drug development is a risky business. More than half of candidate drugs that look promising in the research lab will ultimately fail. More than a quarter of drugs that reach the clinical trial stage will be rejected as ineffective. However, the wealth of genomic information now available through public databases - in particular, the rapidly growing number of known associations between diseases and specific genes - may significantly improve the drug-development success rate.  At least, success rates will improve if drug developers let genomics guide their choice of molecular targets for research, according to a team of pharmaceutical industry and academic scientists.

(Ernesto del Aguila, NHGRI)

Within 10 years, we’ll have the capacity to check more frequently in a readily available fashion. And that is going to enable us to use appropriate combination therapies and also combine immunotherapies and targeted therapies. That’s where we’re going. I’m very hopeful!





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Another Evil TV Geneticist on Netflix’s “Between”

1000px-Mad_scientist.svgTen years ago this month, I attended the Catalyst Workshop at the American Film Institute. The week-long program taught screenwriting to a dozen scientists, with the hope that we’d somehow help Hollywood get the science right.

But what we learned during that fabulous week, dissecting films such as The Day After Tomorrow,”  meeting top studio people and even pitching ideas, is that the science just doesn’t matter. Although I agree that story and characters are paramount, getting the science right doesn’t take much effort, and can not only improve plausibility, but also accurately portray scientists. Geneticists in particular seem especially vulnerable to villianizing.

My latest target for tarnishing the image of geneticists is Between,” a six-episode Netflix offering from Canada. (Yes, I know Halle Berry’s hybrid son on Extant has something to do with a virus, but I gave up two episodes ago.)

Between” is an amalgam of familiar themes. It’s Logan’s Run, Under The Dome, and Lord of the Flies, with a small town setting like that of Wayward Pines, which I blogged about recently. And like those shows, the focus is on the characters and their relationships, with the predicament a backdrop that fuels the interactions.

So now we have Between. In the town of Pretty Lake, over the course of a few days, everyone aged 22 and older suddenly gasps, bleeds from the nose, and dies. The government quarantines the town and the young folk pile up the bodies of their elders and have a huge bonfire. Early in episode one, a main character, a geeky young man named, of course, Adam, mentions his father, a mysteriously missing geneticist. This is repeated throughout the early episodes. Foreshadow the mad scientist.

A nice touch is the accurate depiction of a major character who has Down syndrome. But one scene dangerously got insulin shock ass backwards. A boy with type 1 diabetes collapses from days without insulin and everyone yells “He’s in insulin shock! Give him candy!” Without insulin, how would his cells take up the glucose? Who vetted that script?

Soon, the people in Pretty Lake and the talking heads on their screens deem the culprit a virus. My husband Larry (a chemist) and I hung on through all six episodes to learn exactly how a virus could tell that a person has reached age 22.

We learn in the final episode, when the crazy nameless geneticist shows up via a tunnel that perhaps comes from Wayward Pines, that he engineered the virus. He cleverly included a bit of his own DNA so that he and his son would be immune. Note to the show’s writers: a parent and a child are not genetically identical. Nor do they have the same exposures guiding development of their immune systems.

The evil geneticist was working alone on the virus, because the government sends in unwitting workers wielding needles to “vaccinate” the town’s young survivors, supposedly so the quarantine can be lifted. But no. The shots will kill the young people to protect the rest of the world, as the clueless shotgivers over age 21 become victims, bleeding and dropping.

Larry and I were sorely disappointed with the ending, which did nothing to satisfy the craving of the scientifically-minded to understand how things work.

The geneticist explains how the virus kills people over 21 with a lot of posturing, emitting a barrage of inappropriate technical terms, concluding inexplicably with something about the ozone layer. It all speeds by too fast to process, but the spouting renegade geneticist seems to have invented the virus to fight overpopulation. I think. The focus is much more on teen angst involving a pregnancy and jealousy than how a virus can tell how old someone is.

When Adam parrots his dad’s message to the others, that the killer virus homes in on “the biological clock,” everyone nods with comprehension. But that term refers to circadian and other biorhythms, not a FitBit like contraption embedded in our spleens that flashes our exact ages. Basic Bio 101 writers! But it’s easy to see how that sort of error might have come up: oversimplification in a news release, which means oversimplification in the articles that spawn from it. The news release headline “Leicester scientists to unlock the secrets of the biological clock” actually refers to telomeres, the tips of chromosomes that whittle down with increasing age. Aha!



The only reason that I watched “Between” to begin with was in anticipation of using telomeres in an apocalypse story. Shrinking chromosome tips are like cellular tree rings in reverse, disappearing rather than accruing with the passage of time. With repeats of TTAGGG lopped off one by one from chromosome ends as time goes on, marking the number of cell divisions, telomeres are more quantitative than gray hairs, achy joints, and wrinkles.

In telomeres, Nature provided the perfect plot point, if only the show’s writers had looked.

The telomere clock dates back to the famous “Hayflick Limit” of 40 to 60 mitoses for cells in culture. In the 1950s, Leonard Hayflick, PhD, was a young researcher at the Wistar Institute in Philadelphia. He wanted to see what the fluid around cancer cells would do to normal cells from human embryos and fetuses. At that time all cells were thought to be immortal, dividing unceasingly. “Today if I did that using federal research dollars to grow tissue from human embryos or fetuses, I would go to jail,” he told me a few years ago for my essay collection.

800px-Wooden_hourglass_3Hayflick had wanted to run replicates of his experiment simultaneously, but the supply of material was erratic. “In my incubator at any given time, I’d have 12 to 20 cultures going, each marked with a different start date.

He soon discovered something strange. “Despite the fact that I used the same technician, the same glassware, and the same media, the cells in culture the longest stopped dividing, while the young cultures luxuriated. That shouldn’t happen. It intrigued me, so I began to look at what was going on.”

Hayflick’s fetal cells died after being moved a certain number of times, each move triggering cell division. He and colleague Paul Moorhead repeated their astonishing experiments over and over, with the same results – cells obeyed some sort of internal clock that marks the number of cell divisions. Freeze cells at division 20, and when thawed, they’d pick up where they left off, dividing 20 to 40 more times.

But it’s hard to change dogma and get published. And so Hayflick and Moorhead “sent the luxuriating cultures – the young ones – to the grey eminences of the field. We would tell them, ‘by May 20th to 30th, the cells are going to die.’ When the phone started ringing between May 20th and 30th, we decided to publish. If our work went up in flames, we’d be in the company of the grey eminences,” Hayflick told me. After a stinging rejection from one journal, the findings were published in Experimental Cell Research in 1961.

Discovery of the Hayflick limit founded what we now call telomere biology. Many others, including Elizabeth Blackburn, Carol Greider, and Jack Szostack, who shared the Nobel Prize for Physiology or Medicine in 2009, discovered the DNA sequence of human telomeres and how they function as fuses, marking biological time. DNA polymerase cannot replicate DNA at the end of a strand, unless an enzyme called telomerase tacks on more repeats – as happens in cancer cells. So Pretty Lake might have had a few cancer patients hanging around with the quarreling teens and kids. Their chromosome tips would appear young.


(Claus Azzalin, ISREC)

(Claus Azzalin, ISREC)

Larry and I eagerly awaited a character turning 22 to find out how the virus tracks time. Indeed, a pretty and popular teacher celebrates her 22nd birthday midway through episode 4, and sure enough, within minutes, spews nasal blood and expires. How could that have happened? After all, telomere shrinkage is not a discrete and uniform phenomenon. All 21-year-olds don’t have x number of TTAGGGs and a 22-year-old x-1.

I’m imagining deploying a virus that targets the telomeres using a form of genome editing (CRISPR/cas-9, TALENs, or zinc finger nucleases) and only integrating into a host chromosome if the number of repeats is below a certain threshhold. Then, the virus induces hemorrhage, perhaps by turning off transcription of various clotting factors. (Readers please elaborate or pose alternate hypotheses.)

Reviewers trashed Between for a lot of reasons – too derivative, “ho-hum,” a “familiar ensemble soap opera with conspiracy-theory embroidery,” and Hollywood Reporter’s “It’s the end of the world as they know it, and viewers won’t care.” None that I could find mentioned the spotty science.

Scientists don't create monsters.

Scientists don’t create monsters.

I’m disturbed about the missed opportunity to imagine how a virus could take out an entire huge age cohort of humanity. But I’m much more disturbed about the tired stereotype of the mad scientist, especially the ego-driven geneticist who tailors a mysterious and dangerous virus to control human population growth. It’s not only absurd, but in this age of Ebola epidemics, and fear of vaccines and genetic modification, the ideas behind Between and the events at Pretty Lake are downright dangerous.

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Disappearing Down Syndrome, Genetic Counseling, and Textbook Coverage

Doctor and Patient with DNALast week, several people sent me a perspective piece by bioethicist Art Caplan in PLOS Biology, “Chloe’s Law: A Powerful Legislative Movement Challenging a Core Ethical Norm of Genetic Testing.” The concise and compelling article considers legislation to mandate that genetic counselors talk to their patients more about positive aspects of having a child with trisomy 21 Down syndrome.

Studies show that as availability of prenatal screening (for risk) and testing (for diagnosis) for the condition have increased, births of affected children have decreased. That is, most pregnant women who learn that the fetus has trisomy 21 Down syndrome end the pregnancy. Yet genetic counseling is, historically, largely value-neutral or “non-directive.” Offer the medical facts, explain how tests work and what results mean, listen, and try to intuit the patient’s views to guide word choices. (“Termination” vs “abortion,” for example). Answer questions, but don’t try to sway clinical decision-making.

At least two hypotheses can explain the declining numbers of newborns with trisomy 21.

#1: Genetic counseling is influencing decisions to end affected pregnancies. That’s the assumption behind the legislation that Dr. Caplan discusses.

#2: Parents-to-be and the general public do have access to a great deal of information about Down syndrome and many of them make informed choices. They are electing not to bring children into the world who would face a high likelihood of having certain medical and cognitive problems.

I concur with Dr. Caplan that mandating genetic counselors to more positively spin life with trisomy 21 Down syndrome may obscure the medical and scientific facts, misleading patients.

booksPLOS BLOGS suggested that I weigh in on the matter, and I can, from two perspectives that complement Dr. Caplan’s. I’ve been providing genetic counseling since 1984 for a private ob/gyn practice, and I’ve written eleven editions of a human genetics textbook for non-science majors, starting in 1993.

Throughout the 1980s and 1990s, I often met with women who were of “advanced maternal age” (35+) explaining the benefits and risks of having the invasive procedures amniocentesis or chorionic villus sampling (CVS) to check fetal chromosomes. But since the Internet arrived, I do very little counseling of this type because patients can learn much of what I’d tell them on their own. Today patients can know more about genetics than their physicians.

The editions of my textbook chronicle the possible link between the increase in prenatal testing and the shrinking population of people with trisomy 21. Each new edition arises from updating and a wealth of feedback: from instructors and students, from researchers I interview, essays contributed by families, and most importantly, what I’ve learned at professional meetings, where talks can be months ahead of publications.

Like genetic counseling, textbook coverage of trisomy 21 already presents the negatives and positives.

21_trisomy_-_Down_syndromeMost of my book’s information about trisomy 21 is under the heading “Abnormal Chromosome Number.” I can’t be politically correct about that – normal means “common type” and an extra chromosome is not common. The section expanded abruptly at edition 4 (2001) as chromosome maps filled in with findings from the first sequenced human genomes. But the introduction remains historically accurate, even if the language is offensive today:

“The characteristic slanted eyes and flat face of the Down syndrome patient prompted Sir John Langdon Hayden Down to coin the inaccurate term ‘mongolism’ when he described the syndrome in the 1880s. As the medical superintendent of a facility for the profoundly mentally retarded, Down noted that about 10% of his patients resembled people of the Mongolian race. The resemblance is coincidental. Characteristic facial features are associated with many inherited disorders. Males and females of all races can have Down syndrome.”

Early editions then described the signs and symptoms, followed with: “These people tend to have warm, loving personalities and enjoy art and music. Intelligence varies greatly, from profound mental retardation, to those who can follow simple directions, read, and use a computer. One young man with Down syndrome graduated from junior college; another starred in a television series.”

DrillIn the mid editions I added comments from parents that addressed the subtleties of the condition. “He once dialed 911 when he stubbed his toe, because he’d been told to do just that when he was hurt,” one mother told me. I chose photos that showed young people with Down syndrome doing things – cooking, painting, reading, a little girl banging a toy xylophone. But then I had to respond to reviewers’ criticism that students couldn’t distinguish the “stories” from “what they had to know for the test.” Gradually, the human details that I so love to write about became boxed readings, captions, and tables.

Responding again to reviewer feedback, I shortened coverage of what parents can do to help their child, instead focusing on the science. Edition one mentioned the value of hanging a colored mobile over a child’s crib. That went. Edition eleven explains how researchers have harnessed X inactivation to shut off the extra chromosome 21 in cells of people with Down syndrome, providing a new way to study the pathogenesis. But I never sacrificed the humanity. Opposite a figure on the new technique a photo shows a young woman intently painting a portrait of a tree. The caption: “Many years ago, people with Down syndrome were institutionalized. Today, thanks to tremendous strides in both medical care and special education, people with the condition can hold jobs and attend college. This young lady enjoys painting.

I often give patients pages from my textbook, because it offers both sides. The coverage has always included the hard facts that genetic counselors impart: “About half of babies with Down syndrome die before one year of age, often due to malformations of the heart or kidneys. Other patients must undergo heart surgery or suffer often from common illnesses.” Complications also include poor immunity, intestinal blockages, increased leukemia risk, and the high risk of developing Alzheimer disease in later years. But then the balance: “However, some people with Down syndrome are relatively happy, healthy children and young adults. Unfortunately, the test that diagnoses Down syndrome in a fetus cannot detect how severely affected the child will be. The decision of whether to terminate such a pregnancy or raise a child with Down syndrome is very difficult.” 

ageThe book is more about the science than counseling, explaining chromosome imbalances and the puzzling maternal age effect. We’ve come far from the 1909 study that blamed “maternal reproductive exhaustion.” And the list of genes implicated in the syndrome has grown as the human genome has given up more of its secrets. Before that, we could only deduce the responsible genes from individuals who had partial third copies of  chromosome 21.

Bioethics explosively entered the Down syndrome coverage in edition 9 (2010). A boxed reading analyzed a study from Denmark cited in Dr. Caplan’s article. Government researchers there tracked trisomy 21 cases after broadening availability of screening and diagnostic testing. From 2000 to 2006, the number of affected newborns was halved, those diagnosed prenatally increased by nearly a third, and the number of diagnostic tests (CVS and amniocentesis, which are more invasive than maternal blood test screening) fell by half.

The trisomy 21 story really changed in the current edition, with the boxed reading “Will trisomy 21 Down syndrome disappear?” It considers the impact of screening cell-free DNA in the maternal circulation for fetal DNA. Available since 2011, it’s leading to diagnoses in women under 35, while enabling many pregnant women over 35 to avoid invasive tests. The box quotes two New Zealand researchers who published a paper in May 2013 that enraged several groups into demanding the bioethicists’ resignations. To quote from the paper would be out of context. But they say what I suspect at least some genetic counseling patients are thinking when weighing their options and choosing to end pregnancies to avoid the possible medical risks and realities of Down syndrome.

Brian1In the 12th edition of my book, I’ll discuss legislation, like Pennsylvania’s Chloe’s Law, that Dr. Caplan so artfully describes. I agree with him that if laws compel genetic counselors to talk more about the happy healthy xylophone-banging little children, and less about the toddlers who sport scars from heart surgeries or develop leukemia, patients might leave counseling sessions with skewed views of life with an extra chromosome 21.

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Gene Splicing in Lice and the Challenge of Clothing

174px-Body_liceA terrific article recently published in Molecular Biology and Evolution, “Alternative Splice in Alternative Lice,” provides a compelling example of maximizing genome information – adaptation of the louse Pediculus humanus to the new habitat created when our ancestors invented clothing.

Many parents encounter head lice when their children are sent home from school with instructions to get rid of the horrible rice-krispie-like eggs (“nits”) clinging to their scalp hairs. A good washing won’t do it. Medication and clunky combs do very little alone. The sooner the poor parent realizes that meticulous nit-picking is the only solution, the sooner the nightmare ends.

But consider the louse’s point of view.

Nitpicking isn't easy

Nitpicking isn’t easy

Lice live on us so that they can drink our blood, with a little help from bacteria that provide the B vitamins needed to extract maximal nutrients from their meals. Head lice lay their eggs on our hair shafts, gluing them in place. These are the much more common variety. They don’t carry disease, and are more of a colossal annoyance than anything else.

Body lice deposit their eggs in clothing seams, mostly in the armpits and waistline. The nymphs that hatch, looking like tiny adult lice, must move to the skin for their blood meals.

An infestation of body lice may cause an itchy rash if the host has an allergic reaction to the bites, but the tiny beasts can also spread disease — typhus, trench fever, and relapsing fever. Body lice aren’t nearly as easy to acquire as the head lice that easily jump scalps when kids share hats. They’re seen where people can’t bathe or change clothing often enough – homelessness, combat, natural disasters. (Pubic lice, Pthirus pubis, are a different animal entirely and came from gorillas.)

(J. H. Matternes)

(J. H. Matternes)

Since we split from our shared ancestors with chimpanzees about six million years ago, until the invention of clothing about 170,000 years ago, lice enjoyed the vast landscapes of hairy hominins. So how did the insects cope with their shrinking turf?

The two types of lice haven’t (yet) separated into two species to suit their different habitats. They will mate under laboratory conditions, although not in the wild. The lice look alike, at least to us – the body ones are slightly larger.

The louse genome is small and the insect shares 90 percent of its genes with other insect species. Rounding up the usual suspects of evolutionarily-conserved genes, such as those that encode the cytochromes and ribosomal RNAs, found few distinctions between the two types of lice. But considering a genetic mechanism called alternative splicing revealed how lice access their genomes in different ways when confronted with starkly different habitats.

Gene splicing

Gene splicing

Back in 1978, when I was in grad school learning that genes are continuous stretches of protein-encoding DNA, the idea of and evidence for “genes in pieces” arose. This discovery was a game-changer in the history of genetics. At first thought an anomaly, we’ve since learned that in fact most genes come in pieces. Stretches called introns, which do not encode protein, lie between the protein-coding segments, called exons.

Genes mix and match exons by the removal of introns, a little like selecting outfits from a vast wardrobe. This mosaic make-up of genes facilitates rapid genetic change without permanently altering the genome.

Alternative splicing generates new versions of genes in two ways: introns can stay in when they should be jettisoned, or exons skipped. The discovery that exon skipping can counteract a disease-causing mutation has been harnessed to treat disease.

When our ancestors began to cover their nakedness, lice that had previously enjoyed the expanse of the human anatomy found themselves like forest dwellers plunked into a desert. Alternative splicing might have enabled the insects to adapt, according to the new study.

A nit clings to a hair shaft.

A nit clings to a hair shaft.

Araxi Urrutia from the University of Bath and colleagues from the Universities of Illinois, Notre Dame, and Massachusetts found alternative splicing in about a third of the louse’s genes – 3,598 in either head or body lice, 1,415 just in head lice, and 2,183 just in body lice.

The researchers looked first at categories of genes that might be expected to differ between head and body lice – those affecting immunity or reproduction. Immune system genes didn’t differ in expression, but reproductive genes are indeed spliced differently. It makes sense that successfully laying eggs in the seams of fabric is a different skill than doing so along hair shafts.

Next the investigators took a more unbiased approach by identifying broad classes of genes based on function that are spliced differently in head and body lice. This time, they found major differences in development and in the nervous system.

256px-Human_head_louse_eggDistinctions are eclectic. Differences in the lining of the developing ovary affect the relationship of the insect with its endosymbiont, the vitamin-providing bacteria that must survive the more sporadic blood meals that come with the shrinking habitat fabric foists on the insects. Differences in the development of the salivary glands enable body lice to spread the three infectious diseases to their hosts. And the same gene variants of the nervous system that establish the castes of social insects may foster the sensory and behavioral strategies necessary for body lice to survive on the “human clothing environment.”

In social ants, bees, and termites, environmental factors regulate alternative splicing through methylation of regulatory regions of certain genes. Early in development these changes set into motion the nuanced phenotypes that sculpt castes. Might similar alternative splicing have enabled head lice to expand their range?

183px-Pediculus_humanus_on_a_lice_combGiven time and our continued tendency to wear clothes, will the head louse and body louse one day no longer be able to mate?

This paper illustrates why I love science. The work is beautiful in its logic. The researchers even posed an alternate hypothesis: that the stress of  living on clothing causes a general upheaval of the alternative splicing process. But that wouldn’t explain the consistent findings.

The very best science explains what we observe yet raises further questions – that’s why the phrase “scientific proof” makes me cringe. The investigation of “alternative splice in alternative lice” also provides yet another glorious illustration of the adaptation that could lead to evolutionary change.

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Midsummer Updates at DNA Science

Sonn and grandson (4)Summer is half over, so I thought I’d update a few posts.

A year ago, I frantically wrote about my young friend in Liberia, Emmanuel Gokpolu, and his pleas to help stop Ebola. Emmanuel and his loved ones survived the epidemic. When Eman’s medical education stopped when schools shut and several instructors died, he and his friends took to the streets to spread the word about how to avoid infection. The people of Liberia were saving themselves before the US began to take things seriously, only when the first case happened here.

Medical school in Monrovia has started up again for Eman, but only part time due to loss of people and resources. So he’s looking to continue his education, perhaps in Ghana, South Africa, or Nigeria. Even though Ebola has ebbed to a few cases, infectious disease is a way of life in Liberia. Eman spent his birthday last week recovering from malaria and typhoid fever. He says hi!

Great news! An article in The Lancet just announced a very promising Ebola vaccine!

On January 1, DNA Science covered an inherited disorder called adult polyglucosan body disease. It’s often misdiagnosed, because the symptoms are common. Dragging feet = ALS. Numb extremities = peripheral neuropathy. Numbness + fatigue = MS.

Researchers at Rabin Medical Center in Israel report in the current Journal of Neurology on 30 individuals with APBD, all initially misdiagnosed. Nearly a third had undergone futile, incorrect treatment. More than half of the men were told their urinary frequency was due to an enlarged prostate – some even had the organ removed!

The investigators blame the errors on “physicians’ unfamiliarity with the typical clinical and imaging features of APBD.” To remedy that, the Adult Polyglucosan Body Disease Research Foundation has developed a checklist of symptoms to help neurologists identify the zebras among the horses. And Ruth Kornreich, MD, associate professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mt. Sinai and colleagues recently determined that the carrier rate for APBD in the Ashkenazi Jewish population is a whopping 1 in 68, and have added it to their genetic screening panel.



Back at the beginning of the year, I wrote that “The APBD story offers a powerful example of the evolution of classifying disease by phenotype to the precision of classifying by genotype.” Perhaps because of President Obama mention of “precision medicine” in his state of the union address a few weeks later, an Israeli company has offered to support development of treatments for APBD. I don’t know any details, but the much-needed funding depends upon establishing a patient registry of 200 individuals, and needs more people to sign up.

So … if you have numbness, cramps, stiffness, or a heavy feeling in your hands, feet, arms, and/or legs; muscles that are twitchy or sore; fatigue; foot drag; stumbling; and urinary frequency, please check out the foundation and talk to your health care provider about the possibility that you may have this condition. Sign up for the registry at!

Wayward_Pines,_a.k.a_Agassiz,_BCLast week’s post concerned the ending of the Fox TV series Wayward Pines, in which the remnants of humanity are catapulted (via freezing) 2,000 years in the future, to battle the aberrant creatures that our species will become.

The ending didn’t disappoint. The “first generation,” the high school crowd being groomed to be the future, had more or less stayed in the background, but then they amassed and emerged to get rid of the elders. Rather than the peaceful, willing drifting off to Carousel of over-30s depicted in the dystopia of Logan’s Run, the older folk of Wayward Pines were murdered. The very last scene shows a few mangled characters displayed on light poles for all to see, like the final scene of the film Spartacus with bodies splayed on crosses.

I found the ending of offing the elders disturbingly relatable. Try looking for a job if you’re over 55. Check out the photos on LinkedIn. For a variation on this theme and a great summer read, try The Knockoff. A 40-something executive editor at a Vogue-like magazine returns to work after time off for cancer treatment to discover that her 25-year-old former assistant has gone off to Harvard Business School and is back, in charge, and has turned the magazine into an app.

Knowing what I do about the textbook industry (I just did a podcast on this, On the Difference Between Writing About Science and Science Writing/), the death of magazines and books made from dead trees is more likely than Homo sapiens evolving into the ghouls of Wayward Pines in just 2,000 years.

Eliza and Beckham O'Neill, the cutest kids ever.

Eliza and Beckham O’Neill

I often write about families whose kids have had gene therapy or that have made gene therapy possible for others. Here are a few updates.

Eliza and Beckham O’Neill are still staying at home to avoid contracting any nasty viruses that could keep Eliza out of a gene therapy trial for her  Sanfilippo syndrome type A.

Yesterday I received an invitation to the 17th Annual Canavan Charity Ball, sponsored by Canavan Research Illinois, which means that Max Randell will be turning 18. I can hardly believe it!

Max had gene therapy at 11 months of age for Canavan disease and again a few years later, and will have survived about a decade longer than expected. Sadly, this year’s ball is in memory of Isaac Michael Levin, who died of the disease at just 18 months of age.

Max Randell

Max Randell

“Max and Isaac shared an immediate bond and were able to communicate with each other. It was beautiful and amazing to watch,” wrote Ilyce, Max’s mom, in the invitation. And it’s true. Although Max can only blink, he can communicate – I’ve seen it.

Corey Haas

Corey Haas

Corey Haas, about to turn 15, is doing what kids around my neck of the woods do midsummer – swimming, fishing, hiking. He’s doing great. Without the gene therapy that he had a few years ago, he’d be nearly completely blind, from Leber congenital amaurosis, RPE65 type. The phase 3 clinical trial for that gene therapy is well underway at the University of Pennsylvania and at various stages in several other projects.

Hannah Sames awaits her turn for the gene therapy for giant axonal neuropathy that got underway at the University of North Carolina a few months ago. Although her family is largely responsible for the clinical trial, Hannah’s immune system must be suppressed before she can participate. But the trial for GAN is paving the way for a trial for infantile Batten disease. Dr. Steven Gray is heading up both projects at UNC.

Taylor King

Taylor King

DNA Science has profiled Taylor King, a beautiful young woman who was diagnosed with Batten disease in 2006, at age 7. Her family’s organization Taylor’s Tale has been instrumental in funding gene therapy research at UNC. And thanks to the efforts of Taylor’s mom Sharon and many others, on July 28, the North Carolina General Assembly unanimously voted to establish the state’s Advisory Council on Rare Diseases. Now other states are calling to ask how they did it.

Taylor turns 17 on August 19. Happy birthday Taylor!

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Is Wayward Pines Genetically Plausible?

Wayward_Pines,_a.k.a_Agassiz,_BCTonight is the final episode, ever, of Wayward Pines, the 10-episode FOX television show that’s the best sci-fi I’ve seen since the X-Files.

The series, based on a trilogy by Blake Crouch, has a seemingly simple set-up. Random people, except for an overrepresentation of federal agents such as protagonist Ethan Burke (Matt Dillon), are in car crashes. They awaken in a spooky hospital in a creepy little town in Idaho. Walls (thankfully not a dome), festooned with signs warning that to leave is to die, contain the befuddled but curiously unquestioning townsfolk.

Occasionally, at night, everyone’s landline rings at the same time. This is a “reckoning,” a call to gather in a central square where a throat is slashed for a minor transgression. Graffiti-ing a wall. Mentioning life before Wayward Pines.

The kids – “generation one” – attend an academy run by a headmistress who looks and sounds just like Lisa Kudrow from Friends. I expected her to sing Smelly Cat before realizing she’s really Hope Davis, and terrifyingly manipulative.

When people try to escape the walled town, murderous ghouls flit by and the people vanish.

Idaho_regions_mapSPOILER ALERT!

The phone calls drawing people to reckonings remind me of H.G. Wells’s classic The Time Machine. Its future humanity diverges into the above-ground meek, sleek, blond and blue-eyed Eloi and the dark and dangerous subterranean Morlocks. When the Morlocks are hungry, they sound a siren. The happy Eloi, in a trance, march right into their dens, doomed to become dinner.

But the Wayward Pines gatherings are to prevent being eaten.

After the first 4 episodes, I was certain that Wayward Pines was a resting place for spies, like The Prisoner, another short summer TV series, from 1967. The Prisoner followed a British spy who had just resigned, who’s abducted and sent to a weird, walled prison-like community. I was wrong, and the reveal in episode 5, “The Truth,” knocked me off the couch.

The year is 4028, and the residents of Wayward Pines are all that’s left of humanity, unless pockets of survivors exist (a second season might explore this). Our descendants have become, due to genetic mutations as yet unspecified, “aberrations,” aka “Abbies,” which Wikipedia accurately calls “violent humanoid predators.” Episode 8 ends and 9 begins as an Abbie devours an unfortunate escapee just a few feet outside the walls. In contrast, the Morlocks’ hunting was implied; the 1960 film that scared the crap out of me didn’t actually show the carnage, just the aftermath.

4028? A mere two millennia for humanity to wipe itself out and a new hominin species come to dominate?

128px-Brown,r_time_macine60The dual humanity of The Time Machine, a not-so-subtle allegory of British class distinctions in the early twentieth century, was plausible because the Time Traveler in his contraption zaps ahead to the year 802,701. That’s enough time for geographically separating gene pools with a sprinkling of mutations, plus natural selection acting on sun versus no sun, to have sculpted the two species from one. It’s a duration reminiscent of when several species of Australopithecus co-existed with Homo habilis in Africa, the terrain and other obstacles separating groups sufficiently to allow their differences to persist. At least until our brains developed sufficiently for our forebears to invent travel and for populations to mix.

We can only conjecture how the Eloi and Morlocks branch from humanity. In Wayward Pines, the survivors can thank the mysterious David Pilcher, whose profession is perhaps mad scientist. He had an inkling, back in the 1990s, that the Abbies were coming. According to Donald Trump’s way of associating simultaneous events into causality, Pilcher’s inspiration might have been the grunge movement.

To save humanity, Dr. Pilcher abducted a bunch of people back then and froze them. But unlike Woody Allen’s Miles Monroe in Sleeper, who was frozen like a bag of peas and catapulted two centuries into the future, some of Pilcher’s guests awake in 4014, thaw, learn the truth, and violently kill themselves. So he keeps the others in the deep freeze a little longer, then plants them above his subterranean lab in Wayward Pines. This time, he doesn’t tell the defrosted followers where they are, or why. He knows they can’t handle it, but Matt Dillon disagrees.

How did Dr. Pilcher choose his founding society? Did he invoke a selection process, like in When Worlds Collide or the Twilight Zone episode in which families are chosen to board a spaceship to escape Earth’s imminent destruction?

Heston_and_harrison_planet_of_the_apesThe Abbies of 4028 may share the planet with simians, if one considers the various guises of The Planet of the Apes franchise. The 1968 film’s protagonist Taylor crash-lands in 3978, according to the smashed chronometer on his spaceship. Mark Wahlberg replaced Charlton Heston in Tim Burton’s 2001 version. Mark leaves Earth in 2029, landing on future Earth in 5021. Beneath the Planet of the Apes takes place in 3955, and the TV series in 3085.



The most recent incarnation of the Apes replaced time travel with a runamok gene therapy viral vector that only recently made pet chimp Caesar supersmart. He and his similarly doctored labmates take over within two decades, just in time for a sequel.

Darwin’s Children, another of my favorite books, makes more sense than the errant gene therapy vector and may have inspired it, Greg Bear having published it in 2003. In the world of Darwin’s Children, a retrovirus called Sheva splits humanity, endowing the infected with neurological enhancements that, presumably, will one day enable them to take over, even as discrimination against them surges.

A theoretical way that the human species could diverge rapidly involves a type of chromosome aberration called a Robertsonian translocation. Two different acrosomes – chromosomes with one long arm and one very short arm, numbers 13, 14, 15, 21, and 22 – attach, yielding at first a carrier with one smushed together unusual chromosome, and if carriers mate, some individuals with 44 rather than the normal 46 chromosomes. Without delving into the intricacies of meiosis, the people with 44 chromosomes could not produce viable offspring with the 46-ers and so would technically be an instant separate species, should they decide to procreate. Case Report: Potential Speciation in Humans Involving Robertsonian Translocations details how this can happen. Robertsonian translocations have led to speciation events in rodents and sheep.

But back to the peculiar little town in rural Idaho.



The humans and Abbies apparently diverge over about 134 generations, figuring 30 years as a generation time. That’s about the number of fruit fly generations I tortured as a graduate student. Not really long enough to generate a new species.

So here’s one scenario of the origin and evolution of the Abbies from us. I’m borrowing from other science fiction plots, but notably omitting being impregnated by a space alien and giving birth to a humanoid who looks like Michael Jackson with sparkling eyes and a revved up libido, as happens to Halle Berry’s astronaut character Molly Woods in CBS’s Extant.

1. Something kills a lot of people so the founding Abbie mutations can reasonably become a significant proportion of the population. I suggest a fast-acting flu, as in the terrific new book Station Eleven. The flu decimates about 99.9% of the human population, from 7 billion to 7 million.

2. A massive environmental disaster dismantles infrastructure, like in The Day After Tomorrow. Waves of earthquakes and tornadoes throw up great dust clouds that usher in an extended nuclear winter, as in Robert McCammon’s glorious Swan Song (from 1987, my all-time favorite apocalyptic novel).

3. The prolonged darkness, over time, topples food webs, killing off many species, thereby seeding the eventual cannibalism of the Abbies. Actually, we don’t know if they are a different species because so far they’ve eaten people, not had sex with them. So it might be just hunting.

4. A nice population bottleneck whittles the number of survivors even further, narrowing the gene pool in a random fashion. Then genetic drift, a consequence of sampling from the long-gone whole, and positive natural selection acting on advantageous traits, amplify the impact of certain gene variants.

5. Generations pass. Recessive mutations find themselves paired in individuals, bringing novel traits and new diseases. Meanwhile, new dominant mutations act faster than recessive ones, a point we’ll return to shortly.

6. Nonrandom mating might spread a mutation that offers a survival advantage.


Imagine a settlement of 200 or so people who have survived all the disasters. A boy, let’s call him Adam, has undergone a de novo (i.e. new, not inherited from his parents) autosomal dominant mutation that makes him gorgeous, strong, smart, very horny, and very aggressive. Perhaps Adam has a dominant mutation in a gene that confers “central precocious puberty,” which in Online Mendelian Inheritance in Man, the bible of geneticists, brings “conduct and behavior disorders” in addition to accelerated sexual maturity.

Armadillo-Florida-crop-2009The first mutant to have a lasting impact will be a male, because like Tom the bull who inseminated thousands of cows and Genghis Khan, who famously spread his Y chromosome throughout the world, males can parent more children in a lifetime than females. Then couple Adam and his mutation with Eves prone to ovulating more than one egg at a time, or perhaps even a female capable of conceiving identical quadruplets, like armadillos. The Abbie mutation and other gene variants on its chromosome (transmitted together thanks to linkage disequilibrium) spread through the fledgling population.

Within a few generations, dominant homozygotes arise in whom a dosage effect intensifies the phenotype. As more disasters and plagues ratchet down the biodiversity, the hungry and ever-more aggressive Abbies begin to eat the terrified last remnants of humanity.

Except the residents of Wayward Pines – until tonight, when the walls come down.

Please share your hypotheses!

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“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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