CRISPR Meets iPS: Technologies Converge to Tackle Sickle Cell Disease

sickleResearchers from Johns Hopkins University have teamed two powerful technologies to correct sickle cell disease. Linzhao Cheng and colleagues have deployed CRISPR/Cas-9 on iPS cells to replace the mutant beta globin gene.



CRISPR conjures up images of fried chicken, but it stands for clustered regularly interspaced short palindromic repeats – short repeated DNA sequences interspersed with areas called spacers, like stutters. The pattern attracts an enzyme, Cas9, which is like a molecular scissors that cuts wherever short RNA molecules called “guide RNAs” take it. (For a fuller description, see

(Ernesto del Aguiila, NHGRI)

(Ernesto del Aguiila, NHGRI)

CRISPR directs a natural bacterial immune defense to target genes of interest in a wide variety of species. This “genome editing” tool extends gene therapy by not only delivering healthy copies of genes, but removing the bad ones too.

“iPS” stands for induced pluripotent stem cells. Because they are derived from somatic cells, such as skin fibroblasts, iPS cells can yield other cell types while not irking embryo rights advocates. In a lab dish, human iPS cells can reveal a disease’s start, which researchers from the Harvard Stem Cell Institute first accomplished, for cells from patients with ALS, in 2008.

I’ll leave it to the other science bloggers to explain the details of the new paper. Instead I’ll go back in time, for sickle cell disease has been at key crossroads in the field of human genetics. First, the basics.




Hemoglobin is the protein that carries oxygen in the blood. It consists of two alpha chains and two beta chains.

Sickle cell disease results from a change in codon six in the beta globin gene of CTC to CAC, which replaces the amino acid glutamic acid with valine. That alteration, under low-oxygen conditions, makes the hemoglobin molecules glom into ropelike cables that make the red blood cells that contain them sticky and deformable, then bends them into rigid, fragile, sickle shapes.

The sharply curved cells lodge in narrow blood vessels, cutting off local blood supplies. Once a blockage occurs, behind it oxygen levels fall and sickling speeds up and spreads. The result is great pain in the occluded body parts, especially the hands, feet, and intestines. Bones ache, and depletion of normal red blood cells causes the overwhelming fatigue of anemia.


Sickle cell disease was the first genetic illness understood at the molecular level. In 1904, young medical intern Ernest Irons noted “many pear-shaped and elongated forms” in a blood sample from a dental student in Chicago who had anemia. Irons sketched this first view of sickled cells and showed his supervisor, James Herrick. Alas, Herrick published the work without including Irons and has been credited with the discovery ever since.

In 1949, Linus Pauling discovered that hemoglobin from healthy people and from people with the anemia, when placed in a solution in an electrically charged field, moved to different positions. Hemoglobin molecules from the parents of people with the anemia, who were carriers, moved to both positions.

In 1956, protein chemist Vernon Ingram chopped up the 146-amino-acid-long beta globin subunit and meticulously sequenced the pieces, and found the sickle cell mutation. It was a little like finding a typo in a sentence rather than on a page.


Fetal hemoglobin has two alpha chains and two gamma chains.

Fetal hemoglobin has two alpha chains and two gamma chains.

Embryos, fetuses, and postnatal humans have different hemoglobin molecules. Two of the molecule’s four subunits are replaced during development in sync with changing levels of oxygen in the environment. The genes that encode the various subunits sit beside each other on chromosome 11, turned on and off from embryo to fetus through infancy, like moving fingers on a flute change the note.

The idea that fetal hemoglobin is different dates to two chemistry papers, from 1866 and 1888, that noted that the fetal version doesn’t fall apart in base. Then in 1934, a paper in the Journal of Physiology, “On the occurrence of two kinds of haemoglobin in normal human blood,” described the distinction.

In 1983, researchers identified the methylation patterns that switch hemoglobin types on and off (no, epigenetics is not a new field). And for 40 years, researchers have been co-opting globin chain switching to treat various  “hemoglobinopathies.” The drug hydroxyurea, for example, de-represses fetal hemoglobin genes, reducing the chance of severe sickling.


The relationship between sickle cell disease and malaria is the textbook example of balanced polymorphism: protection against an infectious disease by being a carrier for an inherited disease. DNA Science has covered other examples and more recently in relation to the Ebola epidemic.

The blood of a person with full-blown sickle cell disease is too thick to accommodate the malaria parasite, and the red blood cells too bent to house them. A carrier has enough sickled cells to quell the parasite, but not enough to block circulation and cause the pain and anemia of the inherited disease.

Anthony Allison, a British doctor with expertise in biochemistry and genetics, was investigating blood types in East Africa in 1949, following up a colleague’s observation that sickle cell disease seemed unusually prevalent there. Allison discovered that up to 40% of the members of 35 tribes had sickle cell disease, and all lived in areas where malaria was endemic.

The distributions of sickle cell disease and malaria in Africa coincide.

The distributions of sickle cell disease and malaria in Africa coincide.

Looking at the coinciding maps of the two diseases, he deduced that sickle cell carriers had an advantage. Sure enough, their red blood cells had far fewer malaria parasites than the cells of people with normal hemoglobin. Dr. Allison concluded, “persons with the sickle-cell trait have a considerable natural resistance to infection with Plasmodium falciparum,” in Transactions of the Royal Society of Tropical Medicine and Hygiene, in 1954.


Use of the term “sickle-cell trait” that Allison referenced, which means heterozygotes (carriers), was to have tragic consequences two decades later. I told the story in this Science Progress post from 2008:

“Sickle cell testing between 1970 and 1972 was mandatory in 12 states and targeted African-Americans. Misunderstanding was rampant, perhaps because the term “sickle cell trait” for carriers suggested that their condition was somehow visible. What they carried was stigma. At the time, the disease could not be prevented, tested for before birth, or treated. So why identify carriers? Fortunately the discrimination was short-lived, thanks to passage of the National Sickle Cell Anemia Control Act in 1972. By the 1980s, antibiotic treatment and bone marrow transplant became possible for this painful, but variable, disease.”



I learned off-the-record from a geneticist who would know that a few women committed suicide when told they had the “trait,” but told little else.  The sickle cell testing tragedy was a lesson that reverberates today as we debate how to handle reporting of heterozygote status among secondary (“incidental”) findings in sequenced genomes.


To better study sickle cell disease, although quite a lot was already known, in the 1990s investigators created several strains of transgenic mice that made human hemoglobin. Because early mouse models didn’t exactly recapitulate the human clinical scenario, various attempts to create a transgenic pig with human hemoglobin happened, but I can’t locate much other than this 1996 paper about a pig with hybrid hemoglobin bearing human alpha chains and pig beta chains.

Stem cell transplants can cure sickle cell disease, and antibiotics following newborn screening can prevent infections. Painkillers and transfusions help. For potential treatments lists gene transfer, various supplements and repurposed drugs, and “laying-on-of-hands” in Africa.

CRISPR/iPS blood cells. (Ying Wang, Johns Hopkins Medicine)

CRISPR/iPS blood cells. (Ying Wang, Johns Hopkins Medicine)

This week’s paper about CRISPR and iPS cells may not add much to what we already know about sickle cell disease, but it might provide a way to manipulate oxygen level and watch the hemoglobin subunits segue from embryonic to fetal to adult. That would be cool. It’s also a great proof-of-concept for CRISPR/Cas-9 to cure a single-gene disease in a patient’s own iPS cells, creating a supply of matched replacement cells. Conclude the researchers, “Our results represent a significant step toward the clinical applications of genome editing using patient-derived iPSCs to generate disease-free cells for cell and gene therapies.”


(Much of the history in this post comes from various editions of my textbook, Human Genetics: Concepts and Applications.)

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The Man Who Ate 25 Eggs a Day

SoftBoiledEggHokkaidoTurnipsGarlicButter_(8364603294)Each morning at the retirement community, the healthy 88-year-old man received a delivery of 25 soft-boiled eggs, which he would consume during his day. This had been his way for many years. He’d had one experience of chest pain that might have been angina, but aside from that, he had a healthy cardiovascular system. He recognized that his only problem was psychological: “Eating these eggs ruins my life, but I can’t help it.

I think of the Eggman, a brief case report from 1991 in the New England Journal of Medicine, whenever “news” of cholesterol’s unsuitability as a one-size-fits-all biomarker resurfaces, as it does every few years and did again just last month.

Fred Kern Jr., MD, a gastroenterologist at the University of Colorado School of Medicine, heard about the man and saw an opportunity to study individual differences in how diet affects serum cholesterol level. And so the 88-year-old egg eater joined such famous patients as French-Canadian explorer Alexis St. Martin and Henrietta Lacks.

St. Martin accidentally shot himself in the abdomen in 1822, and when a hole remained after surgery, provided a window through which US Army surgeon William Beaumont could observe and document how the stomach lining changes during digestion. And of course the celebrated cellular descendants of Henrietta Lacks’ cervical cancer live on in labs throughout the world.

Cholesterol -- not the enemy?

Cholesterol — not the enemy?

First, Dr. Kern tested the man’s lipid levels, which were normal: 200 milligrams per deciliter total cholesterol and 142 for LDL. Then he compared the extent to which the man’s body compensated for the cholesterol overload in the 25 daily eggs to that of 11 volunteers who had their cholesterol tested under their usual eating habits and 16 to 18 days after adding five eggs a day. The Eggman was too obsessed to try to go without to help the study. Dr. Kern’s analysis, albeit limited, revealed a lot about how our bodies differ in what we do with lipids.

The 11 volunteers on average absorbed 54.6% of the dietary cholesterol while on their normal diets and 46.4% while on the egg diet. But the 88-year-old absorbed only 18% of his dietary cholesterol. Plus, his liver made less cholesterol than is common and shunted more of it into bile acids (which aid digestion) than did the livers of the volunteers, a metabolic triple whammy that Dr. Kern called “extremely efficient compensatory mechanisms.”

Basically the man’s metabolism adjusted to the overload in a way that kept his blood lipid levels both healthy and constant, the very definition of homeostasis. And he likely isn’t alone.

Genes lie behind our biochemistry, including lipid metabolism. The Eggman from 1991 is a perfect example of how personalized/precision medicine can not only identify individuals at elevated risk for specific diseases, but also those who are genetically protected. Despite recent presidential recognition and the breathless news coverage it spawned, precision medicine is hardly a new idea. It’s genetics. And geneticists have known for decades that in some families, people can have very high serum cholesterol levels yet healthy hearts.

Back in 1991, the case report of the Eggman intrigued me because I, too, ate eggs every day when everyone was pushing cereal and low-fat diets, and my cholesterol levels were just fine. Nor did any of my relatives have any sort of heart disease, not even hypertension. But I still felt guilty eating omelets.


Triglycerides -- the enemy

Triglycerides — the enemy

I continued to eat eggs, and like so many in the US in the 1990s who tried to follow low-fat diets, believing the anti-cholesterol mantra, I gained weight. We were drowning in high-fructose corn syrup, added to everything. But when I dug back into the biochemistry I’d learned in grad school, it quickly became apparent that cutting fats was not at all the best way to lower serum cholesterol or to lose weight. So I began researching the Atkins diet and its low-carb brethren.

In 2004, I began the South Beach Diet. Six months later, my weight and triglycerides had plunged.

Why carbs are bad for blood vessel linings is a matter of logic as well as biochemistry. But it’s a bit circuitous, which may have contributed to the persistent perception that cholesterol is the enemy. It isn’t as simple as what you eat showing up unchanged in your blood or on your frame.

Yes, cholesterol is a major part of the plaque that clogs arteries. It comes from the outside (diet; exogenous) or is made in the body (the liver; endogenous). Here is a good review. I’ll summarize.

Triglycerides, sometimes called just “fat,” consist of one glycerol group bonded to 3 fatty acid tails. They are dismantled during digestion, solubilized by bile acids in the intestines, absorbed into the bloodstream at the intestinal villi, and then the freed fatty acids are used to power muscles or are stored in adipose tissue.

Dietary cholesterol is ultimately ferried to the liver. Meanwhile, the liver is making its own cholesterol — from digested triglycerides. So a low-fat diet can reduce dietary cholesterol, and a statin drug can reduce the liver’s production of cholesterol by blocking the rate-controlling enzyme HMG-CoA reductase.

Gray1086-liverBut consider these facts and relationships:

• Most of the cholesterol in the circulation comes from endogenous production (the liver), not from eating cheeseburgers.

• The liver makes cholesterol from triglycerides.

• 95% of lipids in the diet are triglycerides.

• Carbs (the low-fiber white kind: rice, pasta, potatoes) increase triglyceride levels.

Shouldn’t we be limiting carbs, and not dietary cholesterol? It’s the triglycerides that matter. So how did the vilification of dietary cholesterol arise?


Might the anti-cholesterol push have something to do with the $29 billion global market for statins? (Despite its suffering from “severe generic erosion” as patents expire.) Rampant fear of cholesterol is making statin manufacturers a lot of money.

In January 2012, having not had a check-up in years, I saw a new primary care provider, a nurse practitioner. She did a thorough history, and when my cholesterol came back a few days later at the high end of normal and my HDL not as high as it could have been, she insisted that I needed a statin, stat. That plus a low-fat diet, she admonished.

Atorvastatin40mgWhy?” I answered. “I have zero family history of cardiovascular disease and have no other risk factors. I exercise an hour a day. Low HDL is no longer considered a biomarker. And you mean a low-carb diet, correct?”

She dismissed family history, not the best thing to say to a geneticist. Her refusal to consider my personal risk factors, or lack of them, and her prescribing a drug with rare although serious adverse effects was not something that appealed to me. So, “against medical advice,” I went about my low-carb, statin-free lifestyle.

Three months later, the NP called to pitch statins again. Had I thought it over and changed my mind?

I referred her to an article in a recent Lancet showing that 14 genetic markers combined into a risk score to indicate high HDL – supposedly a sign of hearth health – did not lower heart attack risk, in many patients. This wasn’t news; the report confirmed results of another from 2010. In fact a study of an HDL-boosting drug was halted in 2007 because it actually increased “cardiovascular events.” Perhaps low HDL wasn’t a valid surrogate for heart disease after all? Perhaps the NP should have been reading the medical literature instead of believing drug sales reps, but I suspect she didn’t have the time.

A plaque-lined dissected aorta.

A plaque-lined dissected aorta.

Statins do lower endogenous cholesterol synthesis, and do save lives. But wouldn’t they work best if prescribed only to people who actually need them?

My father, for example, was prescribed a statin at age 84, he too with no risk factors, and he developed muscle pain. That was in 2004. But I just checked the Lipitor package insert, and statins are indeed prescribed to people like him, with no personal or family history of heart disease and the only other risk factor his age — and maybe living into one’s 80s indicates a healthy heart!

How many people are being over- or inappropriately treated by taking these drugs? How many health care providers actually determine an individual patient’s risks? I know health insurers are not big fans of genetic testing, but how many years of one-size-fits-all   statin therapy would it take to equal the cost of genetic tests to direct prescribing?




Lots of labs offer tests for single-gene variants that are important in heart health, such as apolipoprotein E (apoE) and angiotensin converting enzyme (ACE). Panels of tests are available too. GENESIS Center for Medical Genetics, Laboratory of Molecular Genetics screens for 8 genes and Vantari Genetics tests expression of several genes to guide drug selection (pharmacogenomics). GeneDx tests for dozens of single-gene conditions that affect cardiovascular health.

In the past, ordering genetic tests for extremely rare diseases involving lipid metabolism when evaluating an average junk food junkie for statin use made little economic sense.  Lecithin cholesterol acyltransferase deficiency, for example, affects fewer than one in a million people. It causes very low levels of HDL cholesterol and very high total cholesterol – bad news! — but no associated cardiovascular disease.



But the gene-by-gene approach is headed towards extinction, now that the price of exome sequencing (the 85% of the genome that includes most disease-causing genes) has reached the $1,000 mark. A full genome sequencing can now be done in under a day.

Genome analysis takes longer than sequencing, of course, but cloud storage of DNA data will change that. And since tests for single genes that affect lipid metabolism and cardiovascular disease risk have been around for years, why not develop a probe for the relevant subset of the genome to screen statin candidates? Again, could the money insurance companies save on screening out people whom statins wouldn’t help underwrite the cost of sequencing?

Not knowing much about health insurance, I googled to see if any would cover genetic testing to stratify patients for statin use. I didn’t find any, but was thrilled when a statement from one major insurer popped up about genetic testing to identify people at high risk for the severe adverse effect of myopathy, which keeps some people from taking the drugs. Those on high statin doses face a 6-fold increased risk and those over 65 an additional 4-fold increased risk. Some insurers do cover the cost, or for detecting broken-down muscle in the bloodstream every few months, which seems a little late to me.

Paragraph 1 introduces the gene that affects myopathy risk, SLCO1B1. Paragraph 2 claims that “use of statins is associated with approximately 30% reduction in cardiovascular events in a wide variety of populations.” But with genetic testing, aren’t we talking about individuals, not populations?

The document ends with two statements in both italics and boldface. Important! One, that this stuff is complicated so a patient should speak to a physician (patients are dumb, doctors are smart, geneticists don’t exist). Statement two, at the very end after the consumer presumably understands that genetic testing can avoid terrifically painful muscle degradation, I must quote, because it shattered my belief that the insurer was actually going to cover the cost of SLCO1B1 testing, because they bothered to explain it:

Genetic testing for statin-induced myopathy is considered not medically necessary.” This insurer “does not provide coverage for not medically necessary services or procedures.

So there you go. With pharmaceutical giants pushing drugs like statins to a supposedly genetically homogeneous population via doctors who might not have the time or expertise to explore the finer points of lipid genetics, and with insurers years behind the state of DNA science, we might need the hype surrounding precision medicine after all.

Albertus_Verhoesen_Chickens_and_park_vaseCaveat: I’m not an MD. None of the above is meant as medical advice. See your doctor after doing your own research to learn your disease and drug reaction risks. But I’m going to continue to eat my eggs every morning, exercise an hour or more each day, eat veggies and avoid white carbs – and not worry about my cholesterol.

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Fighting Canavan: Honoring Rare Disease Week

baby maxDuring Rare Disease Week, I turn over DNA Science to a family battling a rare inherited disease.

I’ve been following Max Randell, who has Canavan disease, in my human genetics textbook since he was a preschooler – he’s now 17, thanks to gene therapy. Although Max is bright and cherished and happy, life has not been easy.

A year ago DNA Science covered how Max’s experience has inspired his younger brother Alex to become a neuroscientist. My gene therapy book tells the story of how a handful of Jewish people escaping Nazi murderers in a Lithuanian ghetto carried the disease to the US, although like any inherited disease it isn’t confined to one group.

Canavan disease is an enzyme deficiency that melts away the myelin that insulates brain neurons. When Max was born, life expectancy was about 8 years old. But today, with excellent speech, occupational, and physical therapy and earlier diagnosis as doctors become more genetics-savvy, most patients with Canavan disease live into their teens or even their twenties.

Here, in honor of Rare Disease Day 2015, is Ilyce Randell, one of the truly amazing parents I’ve met over the past few years who is finding the funding that is necessary to understand, treat, and possibly even stop these diseases — even if they cannot be reversed.

“Trying to explain to someone what it’s like to raise, love, and save a child born with a rare disease is difficult, and painful beyond words. The world of rare diseases can be dark, depressing and lonely. To raise awareness about a specific rare disease is to let the world into your life, into your deepest hopes and dreams, and even your darkest fears.

Rare_Disease_Day_2015_200pxMy beautiful son Max was diagnosed at 4 months of age with an extremely rare disease called Canavan. My first foray into raising awareness about Canavan disease was not my best moment.

I was still new to raising a sick child. My baby was about 6 months old and lying in his stroller. We were in an elevator when two women began telling me how gorgeous he was (imagine cupid – chubby, electric blue eyes with a pile of golden curls). They asked if he was tired. I looked at them and said, “No, he’s not tired, he’s dying.” The elevator doors opened and I walked out.

Looking back, I should have let them feel the joy of seeing such a beautiful baby, but I hurt and I wanted them to know that even though Max looked beautiful and healthy, he was indeed dying. I think I also needed to try out saying it aloud to strangers. That’s when I realized this would be a long and painful process, and one day, if he lived long enough, the stroller would be a wheelchair and he would not look so healthy anymore.

MaxAt the moment I learned of Max’s diagnosis, I decided I would do anything necessary to save his life. After countless interviews, appearances on talk shows, raising millions of dollars for research, experimental gene therapy, experimental medicines, and a million trips to Capitol Hill, Max has already beat the odds. He is now 17-and-a-half years old.

Along the way, I’ve been explaining what Canavan disease is to anyone who would listen. Part of that explanation is always to let people know that Canavan is a very rare disease, not rare as in affects under 200,000 people, but rare as in a couple hundred kids. There is really no money for research besides what we as families are able to raise.

momandboysathm2We have been very successful garnering attention and funding for Canavan disease, but there is still a long way to go. It can be a sad place, but with the sadness of rare disease I have found immeasurable love so pure that the light it shines brightens even the darkest corner of the world. This fight is exhausting, but my baby was born with a rare disease. My job as his mom is to raise awareness about Canavan.

Ilyce Randell, Director
Canavan Research Illinois
PO Box 5823
Buffalo Grove, IL 60089

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GAN Gene Therapy Trial Gets Green Light

Lori and Hannah Sames (Dr. Wendy Josephs)

Lori and Hannah Sames (Dr. Wendy Josephs)

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


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

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

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

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

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

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

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

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

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

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

From Lori Sames, announcing the start of the trial:

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

Taylor King.

Taylor King

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

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

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

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

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

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

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

Lori Sames at the Recombinant DNA Advisory Committee meeting.

Lori Sames at the Recombinant DNA Advisory Committee meeting.

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

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

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

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

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

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

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

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

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Would Charles Darwin Have Used Tinder?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

A female moose might seek a mate with big antlers.

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

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

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

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

Happy Valentine’s Day!

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Remembering The Pre-Vaccine Era: The Diseases of Childhood

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

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

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

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

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

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

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

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

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

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

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

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

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



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


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

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

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

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

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

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

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

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


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

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



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Surveying the Genomic Landscape of Modern Mammals

A rhesus macaque and a Tasmanian devil.

A rhesus macaque and a Tasmanian devil.

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

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



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

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

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

Tree shrew (wikispecies)

Tree shrew (wikispecies)

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

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

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

An evolutionary success

An evolutionary success

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

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

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

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

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

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

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

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

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

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

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From GMOs to GROs: Will Life Find a Way?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The genetic code. (NHGRI)

The genetic code. (NHGRI)

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

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

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

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

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

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

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

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

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

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

1000px-Mad_scientist.svgTHE MEDIA RESPONSE TO GROs

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

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

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

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

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

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

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

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New Miracle Drugs: What Would You Pay?

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

Levi Collazo, before and after taking Kalydeco for CF.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Doing the math for hemophilia B, it’s easy to see how gene therapy will earn out its development cost. This is the less common form of the clotting disorder, affecting 4,000 people in the US.

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

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

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

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

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

Bone loses cells in Gaucher disease.

Bone loses cells in Gaucher disease.

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

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

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

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



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

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

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

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


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

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

Now let’s look at hepatitis C.

Hepatitis C virus

Hepatitis C virus

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

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

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

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

But consider the price.

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

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

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

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

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

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

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

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

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Adult Polyglucosan Body Disease (APBD): A Diagnostic Challenge

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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




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

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

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

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

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

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

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

header-logoPerhaps the rhyming of three of the four letters of APBD, plus the fact that the term “polyglucosan” is broader and much less commonly used than “glycogen,” contributes to protracted diagnostic journeys. The condition may be fairly common, but often misidentified. In one study, among 380 Ashkenazi Jews the carrier rate was 1 in 34.5 — about the same as Tay-Sachs and other “Jewish genetic diseases.” But of course DNA doesn’t know the religious affiliation of the person in which it resides. Anyone can have APBD. doesn’t yet list APBD but will do so soon, and it’s among the 14 glycogen storage disorder tests that Prevention Genetics offers. I wonder how common it is in other populations, and how often it is indeed shoehorned into other diagnostic codes, and patients receiving inappropriate treatments.


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

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

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

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

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

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