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Genetics, Podcasts, Stanford News

Whole genome sequencing: The known knowns and the unknown unknowns

Whole genome sequencing: The known knowns and the unknown unknowns

A few years ago, when I spoke with Euan Ashley, MD, associate professor of medicine and of genetics, about the promise of genomics for diagnosing and treating diseases he agreed that the field was in the wild, wild west. Now, in my latest 1:2:1 podcast with him, I asked how would he describe this moment in time, when so much has changed so quickly in whole genome sequencing (WGS). First, he said, the costs of sequencing the genome have plummeted. “At the point we spoke we were just coming off the $20,000 genome,” he told me. “Which seems remarkable, because we’d just been at… $200,000, and before that at the $2 million genome. In looking around in science… in medicine, I have not seen a technology that has changed that much.”

Euan AshleyAshley recently published a paper that my colleague, Krista Conger, has written about; in it, Ashley and his fellow researchers, Michael Snyder, PhD, professor and chair of genetics, and Thomas Quertermous, MD, professor of medicine, analyzed the whole genomes of 12 healthy people and took note of the degree of sequencing accuracy necessary to make clinical decisions in individuals, the time it took to manually analyze each person’s results and the projected costs of recommended follow-up. Quite clearly, Ashley says, the study shows “there are still some challenges, not that these are non-solvable problems.”

Ashley often cites an infamous quote that Donald Rumsfeld, former Secretary of Defense, said when he was asked about the lack of evidence of Iraqi weapons of mass destruction, as he thinks the questions that Rumsfeld raised about WMDs are analogous to the field of genetics today. Ashley told me:

There are really a number of things that we really know that we know, because they’re genetic variants we’ve seen many times. Also, there are a number of known unknowns… which are genes that we know are a problem but maybe variants we haven’t seen before, so they look pretty suspicious… There [are] the complete unknowns, the unknown unknowns… Many genes about which we really do not know very much at this point in time.

Who would have thought Rumsfeld was laying out the future of WGS and not just WMD’s?

Previously: Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside, Coming soon: A genome test that costs less than a new pair of shoes, Stanford researchers work to translate genetic discoveries into widespread personalized medicine, New recommendations for genetic disclosure released, Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine and You say you want a revolution
Photo of Euan Ashley by Mark Tuschman

Aging, Genetics, Neuroscience, Research, Sleep, Stanford News

Restless legs syndrome, most common in old age, appears to be programmed in the womb

Restless legs syndrome, most common in old age, appears to be programmed in the womb

Restless legsWhile the sleep disorder called “restless legs syndrome” is more typical of older than younger people, it looks as though it’s programmed in the womb. And a group led by Stanford neurologist Juliane Winkelmann, MD, has pinpointed for the first time the anatomical region in the brain where the programming takes place.

Restless legs syndrome, or RLS, is just what it sounds like: a pattern of unpleasant sensations in the legs and the urge to move them. It has been described as a feeling similar to the urge to yawn, except that it’s situated in the legs or arms instead of the upper torso and head.

Estimates vary, but something on the order of one in ten Americans has RLS. Women are twice as likely as men, and older people more likely than young people, to have it. This urge to move around comes in the evening or nighttime, and can be relieved only by – wait for it – moving around. Needless to say, that can cause sleep disturbances. In addition, RLS can lead to depression, anxiety and increased cardiovascular risk.

Very little is known about what actually causes RLS, although it’s known to be highly heritable. Although a number of gene variants (tiny glitches in a person’s DNA sequence) associated with the condition have been discovered, each by itself appears to contribute only a smidgeon of the overall effect, and nobody knows how.

Winkelmann has been exploring the genetic underpinnings of RLS at length and in depth. In a just-published paper in Genome Research, she and her colleagues have shown that one gene variant in particular depresses the expression of a protein involved in organ development and maintenance. The DNA abnormality Winkelmann’s team zeroed in on occurs not on the gene’s coding sequence – the part of the gene that contains the recipe for the protein for which the gene is a blueprint – but rather on a regulatory sequence: a part of the gene that regulates how much of that protein (in this case, the one involved in organ development and maintenance) gets made, and when.

The kicker (pardon my pun) is that the regulatory sequence in question seems to be active only during early brain development and only in a portion of brain that is destined to become the basal ganglia, a brain region well known to be involved in movement.

“Minor alterations in the developing forebrain during early embryonic development are probably leading to a predisposition in the [basal ganglion],” Winkelmann says. “Later in life, during aging, and together with environmental factors, these may lead to the manifestation of the disease.”

(Wondering if you’ve got RLS? Check this out.)

Previously: National poll reveals sleep disorders, use of sleeping aids among ethnic groups, Caucasian women most likely to have restless leg syndrome
Photo by Maxwell Hamilton

Genetics, Research, Stanford News

Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside

Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside

B0001669 DNA sequencing autoradiograph - colouredAs advances in technology drive down the cost of whole-genome sequencing, the potential for the practice to be used in mainstream health care inches closer to reality. New research from Stanford investigated some of the challenges – and highlighted some lifesaving results – of the technique.

In the study, which will be published tomorrow in the Journal of the American Medical Association, researchers examined the whole genomes of a dozen healthy people and calculated how long it took to manually analyze each participant’s results, the projected costs of recommended follow-up medical tests, and the degree of sequencing accuracy necessary to make clinical decisions for each person. My colleague Krista Conger describes the findings in a release:

The researchers estimated a cost of about $17,000 per person to sequence the genome and interpret and analyze the average of nearly 100 genetic variations deemed important enough for follow-up in each person. Each variation required approximately one hour of investigation to assess the relevant scientific literature and determine whether the change was indeed likely to modify disease risk in the individual. After this process, the researchers were left with approximately two to six results they felt could be clinically important; doctors who reviewed the results as part of the study suggested follow-up tests that carried costs of less than $1,000 per person.

In one of the 12 cases, however, the payoff of this intensive process was big: A woman with no family history of breast or ovarian cancer learned she carried a potentially deadly deletion in her BRCA1 gene. After confirmation of the finding in a clinical cancer genetics setting, she was able to take action to reduce her future risk for breast and ovarian cancer.

One significant challenge is the need to decisively determine the sequence of genes already known to be associated with disease. [Postdoctoral scholar and cardiology fellow Frederick Dewey, MD,] and his colleagues found that commercially available whole-genome sequencing does not achieve the accuracy necessary to identify every nucleotide in about 7 to 16 percent of genes known to be associated with increased disease risk. While a degree of uncertainty is allowable during studies of populations, which look for trends by comparing hundreds of genomes, it makes it impossible to make accurate predictions about one individual’s health status.

Conger goes on to note that, while some of the study results are sobering, researchers still believe the field of whole-genome sequencing will eventually transform clinical medicine. Euan Ashley, MD, associate professor of medicine and of genetics, and one of three senior authors of the paper, said in the release:

We need to be very honest about what we can and cannot do at this point in time… It’s clear that if we sequence enough cases, we can change someone’s life. But with this opportunity comes the responsibility to do this right. Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.

Previously: Coming soon: A genome test that costs less than a new pair of shoesStanford researchers work to translate genetic discoveries into widespread personalized medicineNew recommendations for genetic disclosure released and Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine 
Photo by Wellcome Images

Genetics, Neuroscience, Research, Stanford News

X marks the spot, and so does Y: Brain differences, missing or extra sex chromosomes, and gene dosage

X marks the spot, and so does Y: Brain differences, missing or extra sex chromosomes, and gene dosage

X and Ys - smallHow is a gene like a drug? The more there is of it, the bigger the effect. You have to be careful how you spoon it out. Of course, gene “doses” don’t come in teaspoons, they come in chromosomal copy numbers.

You typically have two copies of each gene – one on the chromosome dad gave you, and one on the chromosome you got from mom – although, it must be said, the “flavors” of these copies many not be identical (e.g., specifying blue versus brown eye color).

And sometimes – in fact, often – one copy of a gene is “turned off” altogether, its activation more or less blocked by biochemical stop-signs. That’s about the same as having only one copy, until and unless the light turns green at some point. A particularly pronounced case of single-dose-itis (my word) occurs on the sex chromosomes, designated either X (for female) or Y (for male) because if you view them under a microscope, that’s sort of what they look like. Unlike the other 22 pairs of paternally and maternally derived chromosomes contained in each human cell, X and Y chromosomes actually look noticeably different from one another even at the gross-inspection stage. “Viewed” closer up with the tools of molecular biology, the two versions of the sex chromosome turn out to have large numbers of lengthy stretches that really are different and indeed may be entirely absent on the Y chromosome. Those differences make every cell in a woman’s body different from every cell in a man’s, as UC-Berkeley biologist Art Arnold, PhD, once pointed out at a particularly lively Stanford symposium on gender differences last year.

Still, X and Y chromosomes share plenty of common regions. So a deviation from the usual double chromosome count, even when the extra or missing chromosome is an X or a Y, can make a big difference in the dosages for plenty of genes. One genetic defect called Klinefelter syndrome, characterized by the presence of a Y and two X chromosomes in each cell, leads to an excessive dose of many genes (three copies instead of two, to be specific). Another genetic defect, Turner syndrome, results in each cell containing only a solitary X chromosome – and only a single copy of numerous genes. Both Turner and Klinefelter syndromes are marked by characteristic cognitive deficits.

Allan Reiss, MD, PhD, director of Stanford’s Center for Interdisciplinary Brain Sciences Research, and his colleagues compared the brains of people with Klinefelter and Turner syndromes with those of individuals with normal sex-chromosome counts. They showed in this imaging study in the Journal of Neuroscience, that anatomical aberrations in particular brain regions among people with extra or absent copies of the sex chromosome closely track the neurological deviations associated with these syndromes – and, importantly, that these aberrations may be caused by the gene-dosage differences resulting from variant sex-chromosome counts.

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Humor as a mate-selection strategy for women? and Brain imaging, and the image-management cells that make it possible
Photo by Naberacka

Cardiovascular Medicine, Genetics, Health and Fitness, Men's Health, Stanford News

The ultramarathoner’s heart

The ultramarathoner's heart

Nuttall-trail 2-webThe manufacturer’s warranty on the human heart is about 100 years or 2.5 billion beats. But do ultra-long-distance runners void this warranty when they regularly run races of 50 to 100 miles?

This was the question at the top of my mind as I wrote a tall tale about Mike Nuttall, a visionary Silicon Valley product designer and an ultramarathoner with hereditary heart disease, featured in the cardiovascular health issue of Stanford Medicine. In 2010 he had a heart attack and a triple bypass operation. Then he went on to run one of the most challenging races on the planet.

Was this fearlessness or folly?

An ultramarathoner pushes a body to its outer limits. Bones and joints are pounded. Dehydration can upset the electrolyte system, the delicate balance of salts and fluids that regulates heart, nerve and muscle functions. The heart, the ultramarathoner of organs, goes into overdrive for about 24 hours. But above all, an ultramarathon tests the mind, as a runner strives to override the brain’s overwhelming signals of pain and fatigue.

In the story, there are plenty of opinions from friends and heart experts on the wisdom of Nuttall’s post-heart-attack decision. But I guess, in the end, what he did was personal and heartfelt.

Previously: Study reveals initial findings on health of most extreme runners, Euan Ashley, MD, on personalized medicine for heart disease and Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions
Photo by Bert Keely (Nuttall’s wingman)

Ethics, Fertility, Genetics, In the News, Pregnancy, Stanford News

Daddy, mommy and ? Stanford legal expert weighs in about “three parent” embryos

Daddy, mommy and ? Stanford legal expert weighs in about "three parent" embryos

3519855504_9000d95a2aIt’s an interesting question that got a lot of traction in the media last week. Does the contribution of a tiny amount of DNA from a third person during in vitro fertilization really mean that the resulting child would have three genetic parents? Researchers in Oregon have proposed the technique as a way to avoid genetic diseases arising from faulty mitochondrial DNA by replacing an egg’s mitochondria with one from a second, healthy woman either before or after fertilization with a man’s sperm. They’ve shown that it works in monkeys, and the FDA met last week to consider whether the technique is safe enough to be used in humans.

Yesterday, Stanford law professor and bioethicist Hank Greely, JD, posted a great analysis of the topic on the university’s Law and Biosciences blog, complete with an elegant explanation of the problem for women with mitochondrial DNA mutations:

The mitochondria (high school biology’s “energy powerhouses of the cell”) have their own very short stretch of DNA, separate from the 6.8 billion base pairs found on 46 chromosomes in the cell’s nucleus (the nuclear DNA).  The 16,569 base pairs of the mitochondrial DNA (hereafter “mtDNA”) hold 37 (some say 38) genes, providing instructions for making 13 (or 14) proteins and another 24 RNA molecules.  The full importance of these genes is unknown, but it is clear that some (happily rare) variations in the mtDNA cause quite severe illnesses. Unfortunately, each child gets all of its mitochondria (and hence its mtDNA) in the egg from its mother; if the mother’s mtDNA is dangerously flawed, so will be the mtDNA of all her children. With almost all other genetic diseases, no matter how inevitably the “bad” genetic variation leads to a disease (how “penetrant” the genetic variation is), a woman will have only a 50% or 25% chance of passing on the condition.  With these, her genes can give rise to no healthy children.

Greely gets at the heart of the matter when he compares the statistically minute contribution from the donated mitochondria to a hypothetical child he calls Heather:

I have DNA from four people in each of my cells:  my mother’s mother, my mother’s father, my father’s mother, and my father’s father. Actually, my DNA really came from all eight of my great-grandparents, and all 1024 of my great great great great great great great great grandparents, and all roughly one million of my great (18) grandparents. Yes, all that DNA passed through my (genetic) parents before coming to me, but why does that matter?

Heather gets her DNA from more than two people a bit differently from the way the rest of us do, but so what? How does getting what is, in effect, “gene therapy,” where the gene is delivered in a natural package called the mitochondrion, turn our hypothetical (and healthy) child into a powerful argument against the procedure?

It shouldn’t.  Heather will not be getting superpowers, she will not be in any meaningfully way “designed” (except to avoid a nasty genetic disease), and she will not be given a newly made DNA sequence never before found in the human gene pool. She will get mitochondria with mtDNA that will allow her to have normal health, not a grave disease. That mtDNA will have been taken from a woman, who, though not a source of Heather’s nuclear DNA, is certainly a participant in the human gene pool.

“Heather has three parents” is NOT an argument. It is an irrelevant but attention-getting slogan that is uncritically put forward as, and sometimes mistaken for, a real argument. Yes, the proposed process is a way of bringing forth living and healthy babies that is somewhat new and different, but so were obstetric forceps, (safe) C-sections, and in vitro fertilization. Novelty is not, in itself, a respectable argument against it.

Previously: Medical practice, patents and “custom children”: A look at the future of reproductive medicine, Five million babies and counting: Stanford expert offers conversation on reproductive medicine and Stanford researchers work to increase the odds of in vitro fertilization success
Photo by Christian Pichler

Cardiovascular Medicine, Genetics, Research, Stanford News, Stem Cells, Transplants

Stem cell medicine for hearts? Yes, please, says one amazing family

Stem cell medicine for hearts? Yes, please, says one amazing family

SM image of bird and heartRecently, a medical situation with one of my children had me gnawing my fingernails and laying awake at night waiting for scary-sounding test results. Thankfully, my growing anxiety was relieved after several days by a reassuring phone call from our doctor. Unfortunately, the health concerns of the stars of my most recent magazine story - the Bingham family of eastern Oregon – are not so easily dismissed.

Three of the five Bingham children have a heart condition called dilated cardiomyopathy; two of the three (14-year-old Sierra and 10-year-old Lindsey) have already had heart transplants at Lucile Packard Children’s Hospital Stanford. Their parents, Jason and Stacy, were gracious enough to share their family’s story with me for my article in our most recent issue of Stanford Medicine magazine.

Heart transplants are life-saving, but they come with a lifetime of medication and monitoring. Many physicians feel that cardiac medicine is on the cusp of a revolution – one in which the power of stem cells will be harnessed to help hearts heal themselves, or perhaps even to grow new, perfectly matched organs for transplant. The California Institute for Regenerative Medicine has awarded more than $120 million to pursue potential therapies. No matter how fast any advances occur, however, they can’t come soon enough for the Bingham parents, who are now anxiously monitoring 5-year-old Gage’s battle with the same disease that led to his sisters’ transplants.

At the same time, physicians at the Stanford Center for Inherited Cardiovascular Disease are searching to find the (presumably) genetic cause for the Bingham family’s heart problems through gene sequencing while researchers in the laboratory of Stanford cardiologist and director of the Stanford Cardiovascular Institute Joseph Wu, MD, PhD, work to create induced pluripotent stem cells from the family to better understand the molecular basis of their illnesses.

I’ve been thinking a lot about Jason and Stacy this past week while I faced my own fears for my daughter. I cannot comprehend how strong they have to be for their children. And, although I work daily with many amazing doctors and researchers, I have to say that Jason and Stacy (and other parents like them) are my true heroes.

Previously: Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions, At new Stanford center, revealing dangerous secrets of the heart and Packard Children’s heart transplant family featured tonight on Dateline and
Illustration, which originally appeared in Stanford Medicine, courtesy of Jason Holley

Clinical Trials, Genetics, In the News, Stanford News

Huntington’s therapy discovered at Stanford shows positive results in humans

Huntington's therapy discovered at Stanford shows positive results in humans

There are definite perks to sticking with the same job for several years. For me, it means the chance to see the progression of research findings I first wrote about in their infancy actually enter human testing. Last week Raptor Pharmaceuticals, based in Novato, Calif., reported positive results in a clinical trial of a possible treatment for Huntington’s disease called RP103. RP103 is a delayed-release cysteamine – a compound first identified in 2002 as a potential therapy in the Stanford laboratory of Lawrence Steinman, MD. As I wrote in my release at that time (courtesy of the way-back machine):

By enhancing the brain’s natural protective response to the disease, researchers were able to alleviate the uncontrollable tremors and prolong the lives of mice with a neurological disorder that mimics Huntington’s. Their finding suggests that a similar treatment strategy may be effective in humans.

Raptor (a company which Steinman advises and in which he holds stock options) enrolled 96 patients in an 18-month-long double blind trial pitting RP103 against a placebo, followed by an 18-month period in which all the participants would receive RP103. Eighty-nine patients completed the first 18-month period; those who received the drug appeared to show slower progression in their disease than those who received the placebo.

It will likely still be years before we know whether the potential treatment will clear the necessary hurdles and become clinically available. But as Steinman said to me in a e-mail last week, “It’s very exciting to see this moving forward in humans.”

Previously: Drug found effective in two mouse models of Huntington’s disease, Amyloid, schmamyloid: Stanford MS expert finds dreaded proteins may not be all bad and Potential therapeutic target for Huntington’s disease discovered by researchers in Taiwan, Stanford

Cardiovascular Medicine, Chronic Disease, Genetics, Research, Stanford News

Damage to dead cell disposal system may increase heart disease

Damage to dead cell disposal system may increase heart disease

garbage cansThink of it like taking out the garbage.

That’s the way Stanford researcher Nicholas Leeper, MD, explained to me the findings of his recently published study.

Actually, it’s more helpful to think of the study’s discoveries on the genetics of heart disease as something of a garbage strike – at the molecular level.

Due to a genetic defect, the body’s ability to dispose of its daily tonnage of dead cells gets damaged, and as a result the body’s garbage - in the form of old cells and debris - starts to build up in the walls of its blood vessels. Normally, the body is extremely efficient at taking out the garbage. Two hundred billion cells die every day in our bodies and most get cleared out within a matter of seconds. But when this process breaks down and garbage in the form of necrotic cells starts building up in the walls of blood vessels, it’s not a good thing.

Leeper, a physician and assistant professor of vascular surgery, and colleagues Yoko Kojima, MD, Tom Quertermous, MD, and others set out to discover why genetic variation at the chromosome 9p21 location has been repeatedly identified as the most important commonly inherited DNA sequence for a wide range of cardiovascular diseases including stroke, heart attacks and aneurysms.

Conducting studies in mice with atherosclerosis, the researchers showed that loss of a candidate gene at this locus leads to impaired “efferocytosis” - from the Latin for “take to the grave” – the process by which dead or necrotic cells are removed. Literally, the burying of dead cells. Mice with this genetic variation showed an increase in buildup of these dead cells, further advancing their atherosclerosis as opposed to those that did not have the genetic variation.

In other words, a commonly inherited genetic variant, which is found in 20 percent of the population, contributes to the development of coronary artery disease (also known as coronary atherosclerosis) by stimulating the accumulation of necrotic debris within the evolving plaque. Coronary atherosclerosis is the process by which plaque builds up in the wall of heart vessels, eventually leading to chest pain and potentially lethal heart attacks. Leeper explained it to me further:

If you were born with genetic variation at the 9p21 locus, your risk of heart disease is elevated, though we haven’t understood why. This research gets at that hidden risk. You can be a non-smoker, be thin, have low blood pressure, and still be at risk for a heart attack if you were born with this variant. This work may help explain that inherited risk factor, and more importantly help develop a new therapy to prevent the heritable component of cardiovascular disease.

Photo by shooting brooklyn

Genetics, In the News, Research

An experiment that “treats each person as his or her own experiment”

DNA_Wellcome_ImagesMany of us rely on rudimentary measurements — such as the number on our scale, our cholesterol level, or the ability to fit into our skinny jeans — as feedback about whether we need to exercise more, eat healthier or make other lifestyle changes to maintain our health. But what if we based these decisions on data about our personal genome and information about major organs and biological systems? Could we more effectively prevent chronic diseases?

A pilot project being launched next month by the Institute for Systems Biology in Seattle aims to answer this question. The project, known as the Hundred Person Wellness Project, will sequence the entire genome of 100 healthy people upon enrollment and then collect data on key health metrics at daily and three-month intervals for a total of nine months. Throughout the study, participants will have access to their personal data points and work with wellness coaches, as well as their own doctors, to use the information to make adjustments to their medical treatments or health behaviors.

Some researchers have expressed concerns about the validity of the study because it lacks a control group and allows individuals to make lifestyle changes while the experiment is underway. Nature reports:

[Leroy Hood, MD, PhD, president of the Institute for Systems Biology,] acknowledges the possible problems. But he counters that the existing clinical-trial system is “totally failing” because it cannot control for peoples’ different genetics and environments. The Hundred Person Wellness Project, he adds, recognizes that those differences are paramount, and treats each person as his or her own experiment. “We can follow things very carefully with each person and see how they respond,” he says.

Atul Butte, head of systems medicine at Stanford University School of Medicine in California, is inclined to grant Hood the benefit of the doubt. He says that an innovative study of this kind might indeed pick up the earliest hints of disease: “They may not end up proving that all these individuals benefit from the study in one particular way, but they may end up showing that all these individuals benefit from the study in their own individual ways.”

Previously: Developing the “Internet of Genes” to enable the secure sharing of genomic data, A call to use the “tsunami of biomedical data” to preserve life and enhance health, Atul Butte discusses why big data is a big deal in biomedicine and Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine
Photo by Wellcome Images

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