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Genetics, Pediatrics, Research, Science, Stanford News

Move over CRISPR, there’s a new editor in town: Stanford-devised approach cures hemphilia in mice

Move over CRISPR, there's a new editor in town: Stanford-devised approach cures hemphilia in mice

A lot of attention has been paid lately to the idea of genome editing. This technique allows researchers to precisely modify an animal’s DNA to replace one version of a gene with another, or to add a working copy for a mutated gene. An approach called CRISPR/Cas9 in particular has garnered interest with its ease of use, ability to modify multiple genes, and relatively quick turnaround time when making specific strains of laboratory animals like mice for study.

Now pediatrician and geneticist Mark Kay, MD, PhD, has published  in Nature a new way to conduct genome editing that could give CRISPR a run for its money because it could be both safer and longer-lasting than other methods. As described in our press release:

The approach differs from that of other hailed techniques because it doesn’t require the co-delivery of an enzyme called an endonuclease to clip the recipient’s DNA at specific locations. It also doesn’t rely on the co-insertion of genetic “on” switches called promoters to activate the new gene’s expression.

Inclusion of endonucleases and promoters run the risk of a gamut of adverse effects in the recipient, from cancers if the promoter turns on the wrong gene in the genome to an unwanted immune response geared toward the foreign proteins. The researchers in Kay’s lab, including postdoctoral scholar and study lead author Adi Barzel, PhD, found a way around their use, and showed that it worked to enable mice with hemophilia to produce a missing blood clotting factor:

The technique devised by the researchers uses neither nucleases to cut the DNA nor a promoter to drive expression of the clotting factor gene. Instead, the researchers hitch the expression of the new gene to that of a highly expressed gene in the liver called albumin. The albumin gene makes the albumin protein, which is the most abundant protein in blood. It helps to regulate blood volume and to allow molecules that don’t easily dissolve in water to be transported in the blood.

The researchers used a modified version of a virus commonly used in gene therapy called adeno-associated virus, or AAV. In the modified version, called a viral vector, all viral genes are removed and only the therapeutic genes remain. They also relied on a biological phenomenon known as homologous recombination to insert the clotting factor gene near the albumin gene. By using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

As Kay, who is also a member of the Stanford Cancer Institute, the Stanford Child Health Research Institute and Stanford Bio X, explained, the integration of the clotting factor gene is key to the successful treatment (other clinical trials involving gene therapy for hemophilia rely on the expression of a free floating, unintegrated gene in the nucleus):

The real issue with AAV is that it’s unclear how long gene expression will last when the gene is not integrated into the genome. Infants and children, who would benefit most from treatment, are still growing, and an unintegrated gene could lose its effectiveness because it’s not copied from cell to cell. Furthermore, it’s not possible to re-administer the treatment because patients develop an immune response to AAV. But with integration we could get lifelong expression without fear of cancers or other DNA damage.

Previously: Gene “editing” could correct a host of genetic disorders, Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and Both a doctor and a patient: Stanford physician talks about his hemophilia

Addiction, Emergency Medicine, Health Policy, Research, Stanford News

Assessing the opioid overdose epidemic

Assessing the opioid overdose epidemic

Vicodin bottle Flickr Sharyn MorrowIn recent years, doctors and policy-makers have become aware of the dangers of prescription opioid medications like methadone, oxycodone and hydrocodone (which is sold as OxyContin or Vicodin). In a study published in this month’s JAMA Internal Medicine, Stanford medical student Michael Yokell and Stanford surgeon Nancy Wang, MD, took a new approach to quantifying those dangers.

Many previous studies of the toll of opioids looked at death certificate data and examined trends among deaths due to opioid overdoses, including street drugs like heroin and prescription painkillers. The new study looked at emergency department admissions and found that more than two thirds of ER visits due to overdoses were related to prescription opioids, while heroin overdoses accounted for 16 percent. Moreover, only about 2 percent of cases that made it to the ER died, but more than half the patients needed further hospitalization.

The study also found that those admitted to the emergency room because of opioid overdoses are more likely to have conditions such as chronic breathing problems, heart problems or mental health issues. Yokell explained that it’s important for doctors to be aware of the possibility of overdose and consider prescribing alternatives or discuss the risk of overdose with patients.

Beyond providing better access to emergency medical care and treatments for patients, an important next step to resolving the problem of opioid misuse is to establish or improve statewide prescription monitoring programs. For example, California has a prescription drug-monitoring database called CURES, but not all doctors actively use the program. “We can do a better job of making that database more widely used by physicians in the state.  We need more doctors to sign up and use it. It’s a valuable resource,” said Yokell.

Additionally, many people get access to prescription opioids via fraudulent prescriptions or from dealers that have illegally obtained the drugs – sometimes from breaking into and raiding pharmacies. “It’s important to keep in mind that good prescribing practices are one component of an effective strategy. There are many other ways for people to get their hands on [prescription opioids] and use them inappropriately.”

Although fixing things on the prescription side is important for managing the opioid overdose epidemic, Yokell notes that it’s not enough. Cases that make it to the ER are likely to survive, but Yokell noted that the fear of criminal charges often results in people avoiding medical care for overdoses caused by opioids and that getting this group better access to emergency services and treatment could improve outcomes. Paramedics and doctors have access to the drug naxolone, marketed as Narcan, which is safe and effective treatment for opioid overdose. But “people don’t call 911, so they are dying,” Yokell told me.

Previously: Stanford addiction expert: It’s often a “subtle journey” from prescription-drug use to abuse, Increasing access to an anti-overdose drug and A focus on addiction, the country’s leading cause of accidental death
Photo by Sharyn Morrow

Imaging, Immunology, Infectious Disease, Neuroscience, Research, Stanford News

Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed

Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed

patchbrainHow can you treat a disease when you don’t know what causes it? Such a mystery disease is chronic fatigue syndrome, which not so long ago was written off by many physicians as a psychiatric phenomenon because they just couldn’t figure out what else might be behind it. No one was even able to identify an anatomical or physiological “signature” of the disorder that could distinguish it from any number of medical lookalikes.

“If you don’t understand the disease, you’re throwing darts blindfolded,” Stanford neuroradiologist Mike Zeineh, MD, PhD, told me about a week ago. Zeineh is working to rip that blindfold from CFS researcher’s eyes.

From a release I wrote about some breaking CFS research by Zeineh and his colleagues:

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it’s difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

A study just published in Radiology may help to resolve those ambiguities. Comparing brain images of 15 CFS patients with those from 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing similar symptoms, Zeineh and his colleagues found distinct differences between the brains of patients with CFS and those of healthy people.

The 15 patients were chosen from a group of 200 people with CFS whom Stanford infectious-disease expert Jose Montoya, MD, has been following for several years in an effort to identify the syndrome’s underlying mechanisms and speed the search for treatments. (Montoya is a co-author of the new study.)

In particular, the CFS patients’ brains had less overall white matter (cable-like brain infrastructure devoted to carrying signals rather than processing information), aberrant structure in a portion of a white-matter tract called the right arcuate fasciculus, and thickened gray matter (that’s the data-crunching apparatus of the brain) in the two places where the right arcuate fasciculus originates and terminates.

Exactly what all this means is not clear yet, but it’s unlikely to be spurious. Montoya is excited about the discovery. “In addition to potentially providing the CFS-specific diagnostic biomarker we’ve been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system,” he told me.

No, not a cure yet. But a well-aimed ray of light that can guide long-befuddled CFS dart-throwers in their quest to score a bullseye.

Previously: Unbroken: A chronic-fatigue patient’s long road to recovery, Deciphering the puzzle of chronic-fatigue syndrome and Unraveling the mystery of chronic-fatigue syndrome
Photo by Kai Schreiber

Aging, Mental Health, Parenting, Research

Girls at high risk for developing depression show signs of stress and premature aging

Girls at high risk for developing depression show signs of stress and premature aging

14465-telomeres_newsAs we age and our cells divide, caps at the ends of our chromosomes called telomeres shorten. When a telomere grows too short, it will die or lose its ability to divide, which causes our skin to wrinkle or sag, as well as damage to our organs. Previous research has shown that depression, chronic stress and inflammation can accelerate this process, causing premature aging and making our bodies more susceptible to infections and disease.

In an effort to better understand the connection between stress, depression and changes in the body, Stanford psychologist Ian Gotlib, PhD, and colleagues studied healthy girls with a family history of depression and compared them to a group of their peers without that medical background. During the experiment, researchers measured participants’ stress response through a series of tests and analyzed their DNA samples for telomere length. According to a Stanford Report story:

Before this study, “No one had examined telomere length in young children who are at risk for developing depression,” Gotlib said.

Healthy but high-risk 12-year-old girls had significantly shorter telomeres, a sign of premature aging.

“It’s the equivalent in adults of six years of biological aging,” Gotlib said, but “it’s not at all clear that that makes them 18, because no one has done this measurement in children.”

The researchers are continuing to monitor the girls from the original study. “It’s looking like telomere length is predicting who’s going to become depressed and who’s not,” Gotlib said.

Based on these findings, researchers recommended that girls at high-risk for depression learn stress reduction techniques.

Previously: How meditation can influence gene activity, Shrinking chromosome caps spell aging cells, sniffles, sneezes… and cognitive decline?, Study finds phobias may speed biological aging and Study suggests anticipation of stress may accelerate cellular aging
Photo by Paulius Brazauskas/Shutterstock

Behavioral Science, Cardiovascular Medicine, Medicine and Society, Research, Stanford News

The lonely are more likely to die. But why?

The lonely are more likely to die. But why?

11317715623_e27537b3f3_zLoneliness isn’t healthy — most everyone knows that. But why exactly does isolation lead to disease, or even death? Stanford researcher Sylvia Kreibig, PhD, set out to answer that question by digging through data from the Heart and Soul Study, an inquiry that followed more than 1,000 coronary heart disease patients for about 10 years, starting in 2000.

Turns out that socially isolated patients are 61 percent more likely to die in any given year than other patients, Kreibig and her team found. Yet you don’t need many friends to stave off the ill effects of solitude. Those with at least one to three regular contacts fared no better than the most-social butterfly. Even tossing in factors that affect mortality such as age and weight didn’t affect general conclusion: friendless folks die sooner. But why?

Kreibig’s team, which included Stanford psychologist James Gross, PhD, delved deeper to figure it out.

It isn’t depression. Depression is independently related to mortality, but it couldn’t explain the link between solitude and risk of death. Instead, Kreibig and colleagues found a strong link between several behavior factors such as smoking, omega-3 concentration (a representative of diet quality), and medication adherence and isolation.

“If you are more integrated, you have people around that look after you and care for you, making sure you’re eating healthy foods, not smoking and taking medications as directed,” Kreibig told me. “You yourself as a patient actually have a lot of control over factors that affect your health… Just by integrating some salmon into your diet, you have a better chance of survival.”

The team classified 1,019 patients into four categories of social integration (low, medium, medium-high and high), based on whether or not they had a partner, strength of linkages with family and friends and membership in religious congregations and community groups. Patients in the low category were more likely to smoke, eat unhealthy foods and skip their medications, the study found.

She cautioned that the study, which appears in this month’s issue of Psychosomatic Medicine, demonstrated correlation, not causation. In addition, the patients were primary male and, as they suffered from heart disease, could be affected differently than healthy, or younger, patients.

Next, Kreibig said she plans to examine the emotions related to social isolation and their effect on health.

Previously: The importance of human connection as part of the patient experience, How social media and online communities can improve clinical care for elderly patients and How loneliness can impact the immune system
Photo by Alex Krasavtsev 

Cardiovascular Medicine, Mental Health, Research

The link between mental-health conditions and cardiovascular disease

The link between mental-health conditions and cardiovascular disease

14496537236_932d9a9acd_zA growing body of research has shown the connection between our emotional well-being and physical health. Among the latest findings: Schizophrenia, bipolar disorders and major depressive and anxiety disorders can greatly increase a person’s risk of heart disease and stroke.

In a study presented at this year’s Canadian Cardiovascular Congress in Vancouver, Canada, researchers examined connections between mental-health conditions, use of psychiatric medication, and heart health using data from the Canadian Community Health Survey. Medical News Today reports:

They found that patients who had a mental illness at any point in their life were twice as likely to have had a stroke or experienced heart disease than the general population, while patients who had not experienced heart disease or stroke had a higher long-term risk of cardiovascular disease.

Furthermore, patients who used psychiatric medications for their mental illness were twice as likely to have heart disease and three times as likely to have had a stroke than those who did not use such medications.

“This population is at high risk,” says [Katie Goldie, PhD, lead author of the study and a postdoctoral fellow at the Centre for Addiction and Mental Health in Toronto], “and it’s even greater for people with multiple mental health issues.”

Goldie and colleague said that there are three main factors that contribute to mental-health patients’ increase cardiovascular risk. They are: lifestyle behaviors, such as tobacco and alcohol use, poor diet and physical inactivity; psychiatric medications, which can induce weight gain and inhibit the body from breaking down fats; and inadequate access to health care.

The findings are significant in light of statistics (.pdf) from the National Alliance of Mental Health showing that 1 in 4 adults in the United States experience a mental health disorder in annually and that serious mental illness costs the nation $193.2 billion in lost earnings per year.

Previously: Examining how mental stress on the heart affects men and women differently, Study shows link between traffic noise, heart attack and Study offers insights into how depression may harm the heart
Photo by Holly Lay

Autism, Parenting, Pediatrics, Research, Stanford News

Parents can learn autism therapy in groups to improve kids’ verbal skills, Stanford study shows

Parents can learn autism therapy in groups to improve kids' verbal skills, Stanford study shows

HoldingHandsAutism is more than twice as common than it was 15 years ago. But the number of clinicians who treat the developmental disorder is growing more slowly than the number of new cases, prompting caregivers to look for novel ways to share their expertise as widely as possible.

One possible approach: Teach groups of parents an autism therapy they can deliver at home. A new study from Stanford and Lucile Packard Children’s Hospital Stanford, published today in the Journal of Child Psychology and Psychiatry, found that small groups of parents could learn to deliver a scientifically validated autism treatment to their own children in a short series of classes.

The therapy, called pivotal response training, which has been validated in several prior studies, was targeted to kids’ language skills. The therapy gives parents a structured method for nurturing children’s verbal skills during everyday interactions.

The approach of having parents give treatment is meant to complement, not replace, one-on-one therapy with autism professionals. But it can still be valuable to children and their families, as our press release explains:

“There are two benefits: The child can make progress, and the parents leave the treatment program better equipped to facilitate the child’s development over the course of their daily routines,” said study co-author Grace Gengoux, PhD, clinical assistant professor of psychiatry and behavioral sciences and a psychologist specializing in autism treatment at the hospital. “The ways that parents instinctually interact with children to guide language development may not work for a child with autism, which can frustrate parents. Other studies have shown that learning this treatment reduces parents’ stress and improves their happiness. Parents benefit from knowing how to help their children learn.”

… To use the treatment for building language skills, parents identify something the child wants and systematically reward the child for trying to talk about it. For instance, if the child reaches for a ball, the parent says, “Do you want the ball? Say ‘ball.’”

“The child might say ‘ba,’ and you reward him by giving him the ball,” [lead author Antonio] Hardan, MD, said. “Parents can create opportunities for this treatment to work at the dinner table, in the park, in the car, while they’re out for a walk.”

The researchers are now following up with studies that will give them more information about which children and families are most likely to benefit from this therapeutic approach.

Previously: Using Google Glass to help individuals with autism better understand social cues, Using theater’s sensory experience to help children with autism and “No, I’m not ready yet”: A sister’s translation for her brother with autism
Photo by Wilson X

Cancer, Genetics, Medicine and Society, Research, Stanford News, Women's Health

Screening could slash number of breast cancer cases

Screening could slash number of breast cancer cases

dna-163466_1280Should every newborn baby girl be genetically screened to prevent breast cancer? Obviously, that isn’t cost-effective — yet. But if it were, would it be worthwhile?

A previous study said no. But research published today in Cancer Epidemiology, Biomarkers & Prevention by Stanford researchers suggests otherwise.

Led by senior author Alice Whittemore, PhD, the team examined 86 gene variants known to increase the chances of breast cancer. They created a model that accounted for the prevalence of each variant and the associated risk of breast cancer. Each possible genome was then ranked by the likelihood of developing breast cancer within a woman’s lifetime.

“It was quite a computational feat,” Whittemore told me.

Working with Weiva Sieh, MD, PhD; Joseph Rothstein, PhD; and Valerie McGuire, PhD, the team found that women whose genomes ranked within the top 25 percent of risk include 50 percent of all future breast cancers. Those women would then have the opportunity to get regular mammograms, watch their diets and make childbearing and breast-feeding decisions with the awareness of their higher risk. Some women might even select, as Angelina Jolie did quite publicly, to have their breasts removed.

“The main takeaway message is we can be more optimistic than previously predicted about the value of genomic sequencing,” Whittemore said. “But we still have a way to go in preventing the disease.”

“Our ability to predict the probability of disease based on genetics is the starting point,” Sieh said. “If a girl knew, from birth, what her inborn risk was, she could then make more informed choices to alter her future risk by altering her lifestyle factors. We also need better screening methods and preventative interventions with fewer side effects.”

“We want to focus on those at the highest risk,” Whittemore said.

Previously: Despite genetic advances, detection still key in breast cancer, NIH Director highlights Stanford research on breast cancer surgery choices  and Breast cancer awareness: Beneath the pink packaging 
Photo by PublicDomainPictures

Biomed Bites, Genetics, Research, Stanford News, Videos

DNA architecture fascinates Stanford researcher – and dictates biological outcomes

DNA architecture fascinates Stanford researcher - and dictates biological outcomes

It’s time for the next edition of Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to groundbreaking researchers in a variety of disciplines. 

It’s a puzzle that would delight puzzle master Will Shortz: How do you pack 2 meters of DNA into a container (the nucleus) only .000005 meters wide? Precisely, and according to plan, it seems. Stanford biophysicist Will Greenleaf, PhD, studies the architecture of the genome, building on the knowledge that DNA’s shape effects how a gene is expressed.

In the video above, Greenleaf, now an assistant professor of genetics, explains: “The genes have to be unpacked to be expressed. The mechanics of that are really fascinating.”

Greenleaf is a physics guy, earning a PhD in applied physics at Stanford to build on his undergraduate Harvard physics degree. He has also studied computer science and chemistry, bringing all of this knowledge to bear on demystifying the structure of DNA, and its RNA offshoots. Greenleaf and his team also develop new instruments needed to measure, see and manipulate DNA structure.

This is important for many reasons, but most directly to treat chromatinopathies, or diseases caused by the improper folding or structure of DNA and its associated proteins.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving forward biomedical innovation here.

Previously: Caught in the act! Fast, cheap, high-resolution, easy way to tell which genes a cell is using, “Housekeeping” protein complex mutated in about 1/5 of all human cancers, say Stanford researchers and Mob science: Video game, EteRNA, lets amateurs advance RNA research

Cardiovascular Medicine, Chronic Disease, In the News, Research, Science, Stanford News

How best to treat dialysis patients with heart disease

How best to treat dialysis patients with heart disease

523392_4923732760_zKidney failure patients on dialysis often have other chronic diseases – heart disease topping the list. They’re prescribed an average of 12 pills a day by physicians, according to Stanford nephrologist Tara Chang, MD, and they spend three-to-four hours at a treatment center three times a week connected to an artificial kidney machine.

For Chang, this makes it all the more important that any medication she prescribes for a patient on dialysis is both essential and effective.

The problem is, particularly in the case of treating kidney patients with heart disease, evidence-based treatment guidelines just aren’t available. Kidney doctors are left making best guesses based on guidelines written for the general population.

“Our patients might be different from patients not on dialysis,” said Chang. “Dialysis patients have a lot of heart disease, yet rarely does a cardiology study enroll patients on dialysis, so we just don’t know.”

This was part of the motivation behind Chang’s most recent study examining the use of anti-platelet drugs such as clopidogrel, one of the most commonly prescribed drugs for kidney patients. The researchers looked at the use of anti-platelet medications such as clopidogrel as treatment following stenting procedures to unclog arteries in the heart in 8,458 dialysis patients between 2007 and 2010. The data suggests that longer-duration of drug use may be of benefit to patients on dialysis who get drug-eluding stents but not those who get bare metal stents. Chang told me:

We found that for those who got drug-eluting stents who took the drug for 12 months compared to those who had stopped the drug at some earlier time point, there was a non-statistically significant trend towards lower risks of death and heart attacks. So for this group, following the same guidelines as for the general population may be appropriate. However, we found no indication of benefit with longer duration of anti-platelet drug use for patients on dialysis who got bare metal stents.

About half of the 400,000 patients in the U.S. on dialysis also have coronary artery disease, as referenced in the study. The number of those getting stents inserted to unclog arteries also has increased 50 percent in the past decade, the study states. The results of the study, while not definitive as to exactly how long doctors should prescribe the drug, does stress the need for more clinical research on patients with kidney failure to provide guidance on treatment strategies for heart disease.

“Because our study was not a randomized trial,” said Chang, “we tried to be very measured in how we interpreted the results. What it does point to is the fact that we can’t assume that what works in non-dialysis patients works in dialysis patients. Hopefully our study will help convince researchers to include our dialysis patients in their studies.”

The paper was published this week in the Journal of the American Heart Association.

Previously: Keeping kidney failure patients out of the hospitalStudy shows higher rates of untreated kidney disease among older adults and Study shows daily dialysis may boost patients’ heart function, physical health.
Photo by newslighter

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