Gene Therapy for Blindness Works!

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A TREATMENT ISN’T A CURE — SO WHAT?
An editorial in the NEJM by Alan F. Wright, MD, PhD of the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh sets a negative tone: “Without a highly efficient vector delivery system and sufficient surviving retinal pigment epithelium and photoreceptors, treatment success will be transient.”

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

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

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

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

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

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

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

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

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

Michael Smedley

Michael Smedley

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

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

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

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

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

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AGTC Tackles 3 Eye Diseases with Gene Therapy

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

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

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

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

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

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

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

I spoke recently with AGTC President and CEO Sue Washer.

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

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

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

WHAT IS X-LINKED RETINOSCHISIS, AND HOW CAN GENE THERAPY HELP?

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

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

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

rod and coneHOW WILL GENE THERAPY TREAT ACHROMATOPSIA?

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

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

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

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

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

(Wikimedia)

(Wikimedia)

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

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

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

Eliza O'Neill has San Filippo syndrome type A.

Eliza O’Neill has San Filippo syndrome type A.

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

(Dr. Wendy Josephs)

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

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

Stay tuned …

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Adventures in Stem Cell Land

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

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

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

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

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

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

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

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

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

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

I picked up all sorts of errors on the website:

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

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

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

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

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

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

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

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

It is thinly-veiled pseudoscience.

SOA-arthritisPLAYING THE PATIENT
I thought I’d investigate something I might one day have: osteoarthritis (OA) of the knee.

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

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

So I called.

Blubber harbors mesenchymal stem cells.

Blubber harbors mesenchymal stem cells.

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

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

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

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

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

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

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

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

Liposuction aspirate.

Liposuction aspirate.

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

But how legitimate is it all?

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

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

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

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

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

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

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

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Assessing Breast Cancer Risk: Beyond the Angelina Effect

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

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

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

RISK MUST BE INDIVIDUALIZED

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

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

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

(HEALTH LINK, WMHT)

(Zeke Kubisch, HEALTH LINK, WMHT)

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

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

MANY GENES CONTRIBUTE

Zeke Kubisch, WMHT HEALTH LINE

Zeke Kubisch, WMHT HEALTH LINEMANY GENES CONTRIBUTE

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

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

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

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

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

LOCATION, LOCATION, LOCATION

(NHGRI)

(NHGRI)

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

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

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

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

MORE THAN A DOZEN GENES

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

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

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

THE POLYGENIC COMPONENT

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

(Jane Ades, NHGRI)

(Jane Ades, NHGRI)

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

LET’S NOT FORGET THE ENVIRONMENT
Most cancers are sporadic (non-familial), beginning with two mutations in both copies of a gene in the same cell, sometime after birth. The cause is an accident of DNA replication or a response to an environmental insult. The much rarer familial cancers tend to appear at younger ages because one cancer mutation is inherited, the other a consequence of later mutation in that first errant cell. The 2-hit hypothesis.

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

(NHGRI)

(NHGRI)

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

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

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

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

Crystal_128_calcEXPLORING RISK CALCULATORS
I looked up my own risk using a few breast and ovarian cancer risk calculators. Everyone in my extended family has had cancer of some form, including me, except my sister. But the cancers were all late onset or due to some obvious environmental exposure, like my aunt the chain smoker and sun worshipper, my uncle the long-time radiologist, and me exposed to years of x-rays for orthodontia without appropriate shielding. My comparison is unscientific and apples-and-oranges, and some omissions,  like Susan B. Komen, adapt their tests from the NCI tool.

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

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

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

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

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

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

(NHGRI)

(NHGRI)

NOT A SIMPLE SITUATION

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TRACING TERATOMA ORIGINS LEADS TO ES CELLS

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

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

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

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

Human ES cells (NHGRI)

Human ES cells (NHGRI)

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

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

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

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

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

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

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

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

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

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Autism Gene Discovery Recalls Alzheimer’s and BRCA1 Stories

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

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

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

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

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

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

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

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

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

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

ECHOES OF ALZHEIMER’S AND BRCA1
The new autism study brilliantly uses a handful of unusual families to open a door to the inner workings of autism. Even though the news release calls the FEMF strategy a “novel approach” and “unconventional method,” it actually continues the tradition that first drew me to study genetics – severe or unusual cases that provide insights into disease mechanisms that affect many.

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

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

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

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

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

Alois Alzheimer

Alois Alzheimer

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

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

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

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

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

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Universal Newborn Genome Sequencing and Generation Alpha

Newborn Screening

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

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

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

(NHGRI)

(NHGRI)

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

INITIAL INTENT: DIAGNOSIS

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

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

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

ATCG's Image with Group of PeopleBEYOND THE USUAL SUSPECTS

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

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

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

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

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

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

ACCESS TO GENOME INFORMATION

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

(NHGRI)

(NHGRI)

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

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

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

PRIVACY BREACHES

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

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

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

 (NHGRI)

(NHGRI)

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

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

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

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

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

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

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

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

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

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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.

 

ACRONYMS AND ABBREVIATIONS

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 http://phys.org/news/2014-03-reverse-liver-disorder-mice-mutated.html.)

(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.

HOW SICKLING HAPPENS

Hemoglobin

Hemoglobin

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.

DISCOVERY OF SICKLED HEMOGLOBIN

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.

GLOBIN CHAIN SWITCHING

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 MALARIA CONNECTION

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.

THE DISASTROUS CARRIER SCREEN OF THE 1970s

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.”

(NHGRI)

(NHGRI)

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.

TREATMENTS

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 Clinicaltrials.gov 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.”

Bravo!

(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.

CHOLESTEROL IS AN IMPERFECT BIOMARKER
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 ARE THE ENEMY

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?

Economics.

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.

MY ANTI-STATIN STANCE
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?

(NHGRI)

(NHGRI)

A TARGET FOR PRECISION MEDICINE

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.

(NHGRI)

(NHGRI)

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
www.canavanresearch.org
PO Box 5823
Buffalo Grove, IL 60089
1-800-833-2194
info@canavanresearch.org

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