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Ask Stanford Med, Cardiovascular Medicine, Events, Genetics

A conversation about using genetics to advance cardiovascular medicine

A conversation about using genetics to advance cardiovascular medicine

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In recognition of American Heart Month, Stanford Health Care is hosting a heart fair on Saturday. The free community event includes a number of talks ranging in topic from the latest developments in treating atrial fibrillation to specific issues related to women’s heart health.

During the session on heart-disease prevention, Joshua Knowles, MD, PhD, will deliver a talk titled “How We Can (and Will) Use Genetics to Improve Cardiac Health.” Knowles’ research focuses on familial hypercholesterolemia, a genetic disease that causes a deadly buildup of cholesterol in the arteries. He and colleagues recently launched a project that uses a big-data approach to search electronic medical records and identify patients who may have the potentially fatal heart condition.

To kick off the conversation about preventing heart disease, I contacted Knowles to learn more about how the genomics revolution is changing the cardiovascular medicine landscape and what you can do to determine if you have a genetic heart disorder. Below he explains why heart disease is a “complex interplay between genetics and environment” and what the future may hold with respect to personalized treatments and pharmacogenetics.

Let’s start by talking about your work on familial hypercholesterolemia (FH). How has the understanding of the genetic basis of FH evolved over the last few years, and what key questions remain unanswered?

For FH, there has been a revolution in our understanding. FH causes very elevated cholesterol levels and risk of early onset heart disease. We used to think that it affected 1 in 500 individuals, but recent studies have pointed out that this is probably an underestimate and it may affect as many as 1 in 200 people. This means that there may be as many as 1 million people in the United States who are affected. We have also identified new genes that cause FH, and the identification of some of these genes has directly translated into the development of a new class of drugs (so called PCSK9 inhibitors) to treat this condition.

What steps can patients take to determine if they are at risk of, or may have, a genetic cardiovascular disorder like FH?

The easiest way is to know about your family history of medical conditions- to know what illnesses affected parents, grandparents, uncles, aunts and other relatives. Of course, genes aren’t the only things that are passed in families. Good and bad habits, such as exercise patterns, smoking and diet, are also passed down through the generations. But a family history of heart disease or certain forms of cancer is certainly a risk factor.

Past research suggests that patients with a genetic predisposition to heart disease can significantly reduce their chances of having a heart attack or stroke by making changes to their lifestyle, such as eating a diet rich in fruits and vegetables. Can lifestyle changes overcome genetics?

Heart disease is a result of the complex interplay between genetics and environment – lifestyle, for instance. For some people with specific genetic conditions, such as familial hypercholesterolemia or hypertrophic cardiomyopathy, the effect of genetics tends to dominate the effect of environment because the genetic effect is so large.

For the vast majority of people without these “Mendelian” forms of heart disease, which follow the laws of inheritance were derived by nineteenth-century Austrian monk Gregor Mendel, it’s difficult to determine at an individual level how much of the risk is due to genes and how much is due to environment (this is for things like high blood pressure, high cholesterol, coronary disease). One clue is certainly family history. However, for most of these diseases the genes are not “deterministic” – that is, people are not destined to have these diseases. Some are more at risk than others, but there are certainly ways to mitigate genetic risk through lifestyle choices. Choosing not to smoke and exercising regularly are two examples of ways you can help to greatly minimize genetic risk.

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Immunology, In the News, Nutrition, Pediatrics, Research

Peanut products and babies: Now okay?

Peanut products and babies: Now okay?

peanut butter2 - big

Updated 2-25-15: Allergy expert Sharon Chinthrajah, MD, discussed the study and its implications on KQED’s Forum today:

***

2-24-15: Any parent of young children is likely familiar with the warnings: It’s not okay to give your baby peanut butter, or any other peanut product, before he or she turns one. Don’t do it! These instructions are so imprinted on my brain that I practically did a double-take when I came across headlines about new research suggesting that infants should, indeed, be fed peanut products – in order to prevent the development of peanut allergies.

This isn’t the first time that the benefits of giving allergenic foods to babies have been outlined, but the language surrounding this study has been particularly strong. As the writer of a New York Times blog entry explained, the authors of the study and accompanying editorial “called the results ‘so compelling’ and the rise of peanut allergies ‘so alarming’ that guidelines for how to feed infants at risk of peanut allergies should be revised soon.” He went on to outline the study findings:

In the study, conducted in London, infants 4 to 11 months old who were deemed at high risk of developing a peanut allergy were randomly assigned either to be regularly fed food that contained peanuts or to be denied such food. These feeding patterns continued until the children were 5 years old. Those who consumed the foods that had peanuts in them were far less likely to be allergic to peanuts when they turned 5.

After hearing the news, I reached out to the folks at the Sean N. Parker Center for Allergy Research at Stanford to get their take on the findings. Sharon Chinthrajah, MD, a clinical assistant professor of medicine, explained that this work is the first randomized controlled study to look at how to prevent peanut allergies. She told me:

We’ve all been waiting for the results of this landmark study to confirm the shift in the paradigm of when to introduce foods into the diet. Early introduction of peanut in the right infants can prevent peanut allergy. Dr. [Gideon Lack, the leader of the study] and colleagues were able to show an 80 percent reduction in peanut allergy in children who started eating peanut early and incorporated it into their regular diet.

Chinthrajah believes the guidelines on babies and peanut products should be revised, “because peanut allergies affect 2 percent of our population in the U.S. and most people do not outgrow this allergy.” But, as other experts have done, she cautions that not everyone should introduce peanuts and other foods into their diet early. “Those who are ‘high-risk’ – who have other allergic conditions such as eczema or other food allergies – should consult with their allergist to see if it would be safe to introduce peanut into their child’s diet,” she advised.

Previously: Taking a bite out of food allergies: Stanford doctors exploring new way to help sufferers, Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows, Researchers show how DNA-based test could keep peanut allergy at bay, A mom’s perspective on a food allergy trial and Searching for a cure for pediatric food allergies
Photo by Anna

Neuroscience, Research, Sleep, Stanford News

Stumbling upon circadian rhythms

Stumbling upon circadian rhythms

PrintIn my job as a science writer, I get to hear lots of amazing stories of discovery. In some cases, researchers have worked diligently to solve one question for decades. Others I talk to describe exciting Eureka! moments where their data suddenly made sense. But some of my favorite stories are those where a scientist is studying one thing, only to make an off-the-cuff observation that leads them in a totally new direction.

In researching circadian rhythms for the latest issue of Stanford Medicine magazine, I heard lots of this last kind of story. There are many obvious ways that circadian rhythms influence biology: our sleep cycles, the way our stomachs start to grumble for lunch at the same time every day, and how many plants close their flowers each night. But scientists are also starting to reveal lots of hidden, unexpected ways that circadian rhythms – the natural cycles in living organisms – affect us. Over just the past few years, researchers in disparate fields have made chance observations that have made them think twice about the timing of their experiments; daily circadian cycles in our bodies can affect everything from how we metabolize drugs to how our immune system acts, they’ve found.

Craig Heller, PhD, who co-directs the Stanford Down Syndrome Research Center, told me about how he was testing a new drug to improve memory in mice with Down syndrome. During the course of his experiments, he noticed that mice who received the drug at night didn’t respond the same way as mice that received a dose in the morning. It led him to start investigating the link between learning, memory, and daily sleep cycles. What he discovered doesn’t just have implications for Down syndrome, but for learning and memory more broadly.

Then, sleep researcher Emmanuel Mignot, MD, PhD, of the Stanford Center for Narcolepsy, walked me through the story of how he and other scientists discovered a link between the immune system and narcolepsy. It all started, he explained, after an odd epidemiological observation: narcolepsy was more often diagnosed in the spring than in the fall.

Of course, lots of what we know about how circadian clocks tick along inside our bodies, keeping time with the world around us, comes from tireless, carefully planned out benchwork, and that can’t be discredited. But some of the most surprising new links I describe in my feature come from scientists taking leaps across fields to explain something they found curious. Check out my feature, “Hacking the Biological Clock,” to learn more about what Heller, Mignot, and other scientists have found on these journeys of discovery.

Sarah C.P. Williams is a freelance science writer based in Hawaii.

Previously: Stanford Medicine magazine reports on time’s intersection with health, Study shows altered circadian rhythms in the brains of depressed people and Narcolepsy = autoimmune disease
Illustration by Harry Campbell

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Health Disparities, Health Policy, SMS Unplugged

Minimum wage: More than an economic principle, a driver of health

Minimum wage: More than an economic principle, a driver of health

SMS (“Stanford Medical School”) Unplugged was recently launched as a forum for students to chronicle their experiences in medical school. The student-penned entries appear on Scope once a week; the entire blog series can be found in the SMS Unplugged category.

Gallegos minimum wage sketchI admittedly don’t understand much about the intricacies of economics. But I don’t have to in order to recognize the significance behind Wal-Mart’s decision to raise the minimum pay for its lowest paid hourly employees. In the week following the company’s announcement, plenty has been written about the impact that such a move will have on the company’s success and on local economies. It goes beyond that, however. What I see is the impact that an increase in income can have on the health of working individuals making a minimum wage.

Let’s do some quick math. Current guidelines list the poverty level at $24,250 for a household of four. Federal minimum wage is $7.25/hr. A full-time employee earning minimum wage therefore brings home $15,080. The working class individual, whose spouse stays home to care for their two children since childcare is unaffordable, incredibly falls $9,170 below the recognized poverty level.

This April, Wal-Mart will increase hourly pay to $9.00 and follow this with an increase to $10.00/hr in February 2016. Even then, a family of four with only one working parent will still fall more than $3,000 below the federal poverty level. Yet, the true hardship of poverty can’t be quantified so easily.

What can’t be measured is the stress that surrounds a working family’s paycheck – especially in matters of health. The difficult decision that my patient makes to skip work in order to bring their sick child to clinic, sacrificing a day’s pay, and – worse – their job security. Weighing feelings of worry for their ailing child against the stress of providing financially for the family. Or my patient who struggled through an upset stomach because she couldn’t afford both the medication and the food that she should be taking it with. Choosing health while enduring hunger.

A raise in minimum wage has direct impacts on health. It means the ability to deal with an unexpected expense without risking basic living standards like food, shelter, and transportation. It means having the luxury of buying fresh peaches instead of canned fruit. It means having a warm coat and shoes for winter. It means buying that prescription that’s been pending for months. It means securing the monthly bus pass to get you to work in the first place. For many, however, even the near 38 percent raise announced by Wal-Mart will not lift their families above the federal poverty line. In a situation where pennies and dimes add up, there will still be a significant deficit that will continue to make it improbable (read: impossible) to earn a way out of poverty.

Countless articles can be found online and in print about the need to increase minimum wage. Recently in the political sphere was a push for a $10.10 minimum wage under the Harkin-Miller Bill (Fair Minimum Wage Act). Unfortunately, the bill didn’t pass the Senate. While the bill may not have represented the necessary increase, it was an acknowledgement by some of the direction we need to take- and not just for economic purposes. We must recognize that reductions in financial hardship through fair wages provide a pathway for addressing health disparities and improving health outcomes.

Moises Gallegos is a fourth-year medical student. He’ll be going into emergency medicine, and he’s interested in public-health topics such as health education, health promotion and global health.

Sketch by Moises Gallegos

Genetics, In the News, LGBT, Medicine and Society, Research, Sexual Health

Sex biology redefined: Genes don’t indicate binary sexes

Sex biology redefined: Genes don't indicate binary sexes

14614853884_3d6d1d662a_zImagine being a forty-six-year-old woman pregnant with her third child, whose amniocentesis follow-up shows that half her cells carry male chromosomes. Or a seventy-year-old father of three who learns during a hernia repair that he has a uterus. A recent news feature in Nature mentioned these cases as it elaborated on the spectrum of sex biology. People can be sexed in a non-straightforward way and not even be aware of it; in fact, most probably aren’t. As many as 1 person in 100 has some form of “DSD,” a difference/disorder of sex development.

The simple scenario many of us learned in school is that two X chromosomes make someone female, and an X and a Y chromosome make someone male. These are simplistic ways of thinking about what is scientifically very complex. Anatomy, hormones, cells, and chromosomes (not to mention personal identity convictions) are actually not usually aligned with one binary classification.

The Nature feature collects research that has changed the way biologists understand sex. New technologies in DNA sequencing and cell biology are revealing that chromosomal sex is a process, not an assignation.

As quoted in the article, Eric Vilain, MD, PhD, director of the Center for Gender-Based Biology at UCLA, explains that sex determination is a contest between two opposing networks of gene activity. Changes in the activity or amounts of molecules in the networks can sway the embryo towards or away from the sex seemingly spelled out by the chromosomes. “It has been, in a sense, a philosophical change in our way of looking at sex; that it’s a balance.”

What’s more, studies in mice are showing that the balance of sex manifestation can be shifted even after birth; in fact, it is something actively maintained during the mouse’s whole life.

According to the Nature feature, true intersex disorders, such as those from divergent genes or the inability of cellular receptors to respond to hormones, yield conflicting chromosomal and anatomical sex. But these are rare, about 1 in 4,500. For the 1/100 figure, they used a more inclusive definition of DSDs. More than 25 genes that affect sex development have now been identified, and they have a wide range of variations that affect people in subtle ways. Many differences aren’t even noticed until incidental medical encounters, such as in the opening scenarios (the first was probably caused by twin embryos fusing in the woman’s mother’s womb; the second by a hormonal disorder).

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Research, Science, Stanford News

Stanford researchers show how hijacking an enzyme could help reduce cancer risk

Stanford researchers show how hijacking an enzyme could help reduce cancer risk

Mochly-RosenFor the first time, Stanford researchers figured out a sneaky way to make an enzyme do something it wouldn’t normally do — imitate another enzyme and digest alcohol properly. Their work suggests a possible preventative mechanism for alcohol-related cancers in an at-risk population and is a promising new route for drug discovery.

Daria Mochly-Rosen, PhD, professor in chemical and systems biology, and Che-Hong Chen, PhD, senior research scientist, conducted the study, which was published online yesterday in Proceedings of the National Academy of Sciences.

Enzymes are notoriously choosy, selectively responding to certain molecules that bind precisely in their active site, but the researchers were able to change the selectivity of an enzyme’s active site by “hijacking” it with a small molecule.

Making an enzyme act like another enzyme isn’t just cool. It can have important health consequences for people who have broken enzymes because of genetic mutations.

I wrote about this enzyme deficiency in a press release on the study:

When most people and animals consume alcohol, the body digests it rapidly, within a few hours. One of the byproducts of alcohol metabolism is a chemical called acetylaldehyde. According to the World Health Organization, acetylaldehyde is a Group-1 carcinogen, which means there is a direct link between exposure and cancer.

For most people, acetylaldehyde is not a major health risk — though it can contribute to hangover symptoms — because an enzyme called ALDH2 quickly converts it to a harmless acid. But for some, acetylaldehyde is a big problem.

These people lack a working version of ALDH2 because of a genetic mutation. ALDH2 deficiency is the most common genetic mutation in humans, affecting about 40 percent of East Asians — some 560 million people, or nearly 8 percent of the world’s population. Without a working enzyme, the body cannot clear the toxic acetylaldehyde quickly.

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Chronic Disease, Health Policy, Public Health, Public Safety, Stanford News

New uses for old polymers: Stanford Engineering team uses surgical glove material to make air filters

New uses for old polymers: Stanford Engineering team uses surgical glove material to make air filters

After visiting China and enduring the stifling air pollution, Stanford engineering professor Yi Cui, PhD, wanted to explore solutions to the problem. This week, his team published a paper in the scientific journal Nature Communications, detailing a new kind of highly effective air filter made out of polyacrylonitrile, a synthetic polymer that is used to make surgical gloves.

The researchers used a relatively new technique called electrospinning, or drawing out microscopically thin threads from a liquid to make a lightweight and fairly transparent filter out of PAN. The filter attracts particles from the air, especially those around 2.5 microns – or PM2.5 – which are among the most dangerous for the human respiratory tract.

The researchers make the case for the new PAN air filter pretty eloquently in a press release:

“It was mostly by luck, but we found that PAN had the characteristics we were looking for, and it is breathtakingly strong,” said Po-Chun Hsu, co-author on the study and a graduate student in Cui’s lab.

. . .

“The fiber just keeps accumulating particles, and can collect 10 times its own weight,” said Chong Liu, lead author on the paper and a graduate student in Cui’s lab. “The lifespan of its effectiveness depends on application, but in its current form, our tests suggest it collects particles for probably a week.”

The material collects 99 percent of air particles for up to a week, but is still 70 percent transparent, so it could be used as a window covering. “It might be the first time in years that people in Beijing can open their window and let in a fresh breeze,” Cui said in the statement.

Previously: The high cost of pollution on kids’ healthStudy shows air pollution may increase heart attack risk more than drug useContinuing pollution restrictions used during Beijing Olympics could reduce cancer rates and New insight into asthma-air pollution link
Video by Kurt Hickman

Chronic Disease

Letting go of my secret about Charcot-Marie-Tooth, “the biggest disease no one has heard of”

We’ve partnered with Inspire, a company that builds and manages online support communities for patients and caregivers, to launch a patient-focused series here on Scope. Once a month, patients affected by serious and often rare diseases share their unique stories; this month’s column comes from a patient advocate from Washington.

I’ve tried hundreds of different versions of my story to try to get people to understand. “I walk funny because I have Charcot-Marie-Tooth, also known as CMT. It’s named after the three doctors that discovered it: Charcot – Marie – Tooth. It’s a type of Muscular Dystrophy – but not really… It’s a genetic, progressive, neuromuscular disease that affects my legs and feet, arms and hands – and my diaphragm. It makes me tired. I’m sometimes in a lot of pain. Currently there is no treatment or cure. It’s just something I am living with.” Blah…blah…blah. I can see the person I’m talking with zoning out and I know I’m losing him. That’s hard because I’ve only just recently opened up about my CMT. I want my friends, family and the world to understand why I have struggles and limitations.

I’m 46 years old, and I was diagnosed at 13 years old. It’s been a secret I’ve kept hidden for 33 years.

The outpouring of support I received gave me the confidence and empowerment to get involved in raising awareness of the disease

CMT is by definition a rare disease, affecting fewer than 200,000 people in the U.S. Before the diagnosis, I tripped and fell a lot. When the pediatrician taped on my knee to test my reflexes, nothing happened (I always thought he just must be seeing something I didn’t see because he looked puzzled, but then moved on without commenting). I was constantly spraining my ankles and bandaging my knees from falling so much. Finally, the CMT diagnosis explained it. But it certainly didn’t do anything to help the situation other than confirm that I had a serious disease that would continue to burden my  me. I became a master of making excuses for why I couldn’t join in activities like volleyball, jogging, aerobics, hiking, walk-a-thons, and much more. Social events even upset me, and I became more isolated.

It wasn’t until my disease progressed to the point that I needed braces to help me walk that I could no longer keep my secret. While researching online for bracing options, I discovered the advocacy organization Hereditary Neuropathy Foundation. In finding the foundation, I realized I wasn’t alone: Many others felt as I did. I agreed to conduct a letter-writing campaign, letting friends and family know about the diagnosis and why I wear leg braces; doing so helped people understand why I made changes in my life in order to adapt to my CMT.

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Applied Biotechnology, Bioengineering, Medical Education, Stanford News, Videos

An online film festival for medtech inventors

An online film festival for medtech inventors

biodesign-process

The Stanford Biodesign program recently posted 296 short education videos on medical technology innovation. From needs finding through business planning, it offers entrepreneurs hours of useful advice on developing medical products.

This video library, which was launched with the second edition of the Biodesign textbook, is free to all. Its well-designed online interface makes it easy to access the advice that medtech innovators need, when they need it.

To create the video library, Biodesign hired filmmakers from both inside and outside of Stanford to capture the essence of the 2013-14 Biodesign fellowship program. During this ten-month program, multidisciplinary teams undergo a process of sourcing clinical needs, inventing solutions and planning for implementation of a business strategy. The program’s track record for bringing new medical devices and technologies to patients is impressive: Biodesign fellows have founded more than 30 companies in the last 14 years.

Each three- to four-minute video features interviews with faculty, fellows, CEOs, investors and alumni who have gone on to launch companies. A few of my favorites are:

The Biodesign video library, which was supported by the Walter H. Coulter Foundation, is an extension of the program’s mission — to help train the next generation of leaders in biomedical technology innovation. While the Stanford-based Biodesign program admits only 12 full-time postgraduate fellows a year, now these lessons-learned can be shared with medtech entrepreneurs around the globe. Just B.Y.O.P. (Bring your own popcorn.)

Previously: A medical invention that brings tears to your eyesBiodesign fellows take on night terrors in children, Stanford Biodesign Program releases video series on the FDA systemHeart devices get at mobile makeover
Illustration from Cambridge University Press

Stanford Medicine Resources: