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Genetics, NIH, Research, Science, Stanford News, Technology

Of mice and men: Stanford researchers compare mammals’ genomes to aid human clinical research

Of mice and men: Stanford researchers compare mammals' genomes to aid human clinical research

Scientists have long considered the laboratory mouse one of the best stand-ins for researching human disease because of the animals’ genetic similarity to humans. Now Stanford researchers, as part of a consortium of more than 30 institutions, have confirmed the mouse’s utility in clinical research by showing that the basic principles controlling genes are similar between the two species. However, they also found some important differences.

From our press release on the work:

“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “We are interested in what makes a mouse a mouse and a human a human.”

The research effort, Mouse ENCODE, complements a project called the Encyclopedia of DNA Elements, or ENCODE, both funded by the National Human Genome Research Institute. ENCODE studied specific components in the human genome that guide genes to code for proteins that carry out a cell’s function, a process known as gene expression. Surrounding the protein-coding genes are noncoding regulatory elements, molecules that regulate gene expression by attaching proteins, called transcription factors, to specific regions of DNA.

The Mouse ENCODE consortium annotated the regulatory elements of the mouse genome to make comparisons between the two species. Because many clinical studies and drug discovery use mice as model organisms, understanding the similarities and differences in gene regulation can help researchers understand whether their mouse study applies to humans.

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Aging, Chronic Disease, Pediatrics, Research

“The child is father of the man”: Exploring developmental origins of health and disease

"The child is father of the man": Exploring developmental origins of health and disease

3801281145_1f3fb2c8bf_z Among scientific communities, there is a small but growing segment of research concerned with “DOHaD” – the developmental origins of health and disease. The work usually focuses on how childhood, including birth, the fetal period, and sometimes even pre-conception events, affects a person’s lifelong health and well-being and is the topic of a recent article (subscription required) published in Pediatrics by researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The phrase “the child is father of the man” is a line from William Wordsworth’s “My Heart Leaps Up” and also the title of the article, whose authors added, commendably, “and the mother of the woman.”

DOHaD gained acceptance within the medical community starting with the “Barker Theory” in 1995, when David Barker, MD, showed that babies with low birth weights were at higher risk for coronary heart disease later in life. Prior to his work, the dominant model was that the health of those who survived childhood without major disease or disability was sort of “reset” in adulthood, to decline from then into old age. This is increasingly understood to be a simplistic model.

Resistance to the idea stems from the fact that links between child and adult health are associative and not proven to be causative; therefore, the article’s authors Alan E. Guttmacher, MD, and Tonse N.K. Raju, MD, call for scientists to do more mechanistic research investigating causation, and “more importantly, to devise treatments and preventions, for the many “adult-onset” conditions that actually are rooted in much earlier exposures and events.” Such research is difficult because of the incredible number of variables that occur over an entire lifespan, and even within the category “perinatal risk factors.”

In the piece, the authors describe the importance of DOHaD and how a better understanding of it could affect pediatrics and health care:

Arguably the most important advance in the health care of children, and in establishing pediatrics as a medical specialty, was the cultural awakening that children were not simply small adults. Ironically, DOHaD greatly expands the impact of pediatrics by reversing that shift and focusing on how children actually are smaller versions of the adults they will become.

Once the biological and behavioral pathways that underlie DOHaD are identified and understood, the role of pediatrics should expand in fundamental and powerful ways. Anticipatory guidance in the future will not be just about the next 6 weeks or 6 months or even 6 years of the child’s life, but the entire life span. The pediatrician and other children’s health care providers will inform parenting and behaviors, including diet and exercise, and even prescribe presymptomatic medication targeted to the individual child. The pediatrician will become the gatekeeper to lifelong health.

Photo by Brad Brundage

Big data, Cardiovascular Medicine, Chronic Disease, Research, Science, Stanford News, Videos

Big data approach identifies new stent drug that could help prevent heart attacks

Big data approach identifies new stent drug that could help prevent heart attacks

Ziad Ali, MD, PhD, was a cardiovascular fellow at Stanford with a rather unique skill when a 6-year study published today online in The Journal of Clinical Investigation first began.

The multi-talented physician-scientist – who is now associate director of translational medicine at Columbia University Medical Center – had figured out a way to put tiny little stents into mice with clogged arteries as a PhD student.

The skill would become key as he and colleagues set out to find a better pharmaceutical for the drug-eluting stents that are used in combination with angioplasty to treat coronary artery disease. In order to prevent stent disease, the often serious medical problem caused by stents themselves, chemotherapy drugs were added to bare metal stents. But these drug-eluting stents have their own problems: The drugs work like “hitting a pin with a sledgehemmer,” as Ali describes it, often damaging the lining of the arteries which can lead to heart attacks. As a result, patients are required to take blood thinners for up to a year after the procedure to prevent clots.

“A lot of our patient population is on the elderly side with bad hips or diabetes,” Ali told me. “Once you get a drug-coated stent, you can’t have surgery for a year. And if you stop the blood thinners for any reason, you’re at risk of a stent clotting off. And that actually causes a heart attack. Stent thrombosis has a high mortality rate.”

By using a “big data” computational approach, learning about the genetic pathways involved in coronary artery disease, then testing the new theories on mice models in the lab, researchers were able to pinpoint a potential new treatment for patients: Crizotinib, a pharmaceutical approved by the FDA for treatment in certain cases of lung cancer.

“This could have major clinical impact,” Euan Ashley, MD, PhD, senior author of the study, who discusses the work alongside Ali in the video above, said.

Previously: Euan Ashley discusses harnessing big data to drive innovation for a healthier world, New computing center at Stanford supports big data, Trial results promising for new anti-clotting drug and A call to use the “tsunami of biomedical data” to preserve life and enhance health
Photo in featured entry box by Mark Tuschman

Obesity, Parenting, Pediatrics, Research

Study shows that toddlers benefit from rules about eating habits

Study shows that toddlers benefit from rules about eating habits

toddler_eatingA recent study from pediatrics researchers at the University at Buffalo suggests that toddlers who are faced with parental rules about what to eat develop better eating habits later in their childhood, regardless of the self-restraint they demonstrate. The connection between self-restraint and eating habits has been studied widely in adults and adolescents, but this research is among the first to investigate it in very young children.

The findings suggest that self-restraint in two year-olds doesn’t itself lead to healthier habits by the time the child is four; it must be combined with parental rules about eating. Neha Sharma, a co-author of the paper, explained the significance when presenting the research at ObesityWeek 2014 in Boston, as quoted in a University of Buffalo news release:

It is amazing to see that a parental rule about which types of food a child can and cannot eat could have such a great impact on child eating habits. Without these boundaries set by caregivers, the benefits of high self-regulation on weight gain and childhood obesity could be diminished. This illustrates just how important parental involvement is in influencing child eating habits.

Seventeen percent of American children age 2-19 are obese, as are nearly 35 percent of adults, according to the Center for Disease Control and Prevention. Obesity is well-known as a pressing public health issue, and children who are obese are much less likely to attain healthy weights as adults.

Furthermore, a study published this week in Pediatrics suggests that obese youth are very likely to become obese teens, contrary to a popular idea that overweight adolescents have “baby fat” that will disappear with puberty. Researchers found that a child’s weight at age 11 is a good indicator of his or her weight at age 16: 83 percent of obese fifth-graders remained obese, and 87 percent of normal-weight fifth graders remained at a normal weight five years later.

By setting guidelines and rules for toddlers, parents and caretakers can play a key role in guiding society’s very youngest members towards healthy eating habits with life-long impacts.

Previously: No bribery necessary: Children eat more vegetables when they understand how food affects their bodies, Examining why instilling healthy eating and exercise habits in children may not prevent obesity later in life and How to combat childhood obesity? Try everything
Photo by David Goehring

Aging, Genetics, In the News, Research, Stanford News

“A lot more data” needed to determine what makes supercentenarians live so long

"A lot more data" needed to determine what makes supercentenarians live so long

Scientists from Stanford and elsewhere have been hunting for a genetic explanation for extreme longevity for the past four years and are realizing that it is a more difficult proposition than they initially hoped.

Their research compared the genomes of 17 “supercentenarians” – those who have lived 110 years and beyond – with those of 4,300 “regular” people recorded earlier in a National Institutes of Health study. The study was geared toward finding a single gene or group of genes responsible for a particular trait – in this case longevity – similar to genes which have been found to cause disease or confer immunity. But they have had no luck. Stuart Kim, PhD, a Stanford geneticist and molecular biologist and founder of the Kim Lab for the study of aging, commented in a San Francisco Chronicle piece:

We were looking for a really simple explanation in a single gene, and we know now that it’s a lot more complicated, and it will take a lot more experiments and a lot more data from the genes of more supercentenarians to find out just what might account for their ages.

However, data about the oldest people in the world still suggests that the reason they can live so long has to do with their genes, and not with lifestyle choices. The supercentenarians have average rates of cancer, heart disease, and stroke, although they have escaped many age-related diseases, and their smoking, alcohol, exercise and diet appear no different than among ordinary people. Furthermore, as noted in the article, the parents, siblings and children of the centenarians have also lived well beyond average.

Previously: Unlocking the secrets to human longevity and California’s oldest person helping geneticists uncover key to aging

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

Patients’ reaction to ME/CFS coverage in Stanford Medicine magazine

Patients' reaction to ME/CFS coverage in Stanford Medicine magazine

me-cfs-brain-zeineh

In the last few weeks, Stanford published two articles on chronic fatigue syndrome, a.k.a. myalgic encephalomyelitis, and the outpouring of positive feedback from ME/CFS patients has been tremendous. In my long-form Stanford Medicine story and video, I describe a young woman’s seven-year battle with the disease and the groundbreaking research being done by her physician, José Montoya, MD, and immunologist Mark Davis, PhD, to identify the biomarkers and root causes of ME/CFS. My colleague Bruce Goldman followed up with an elegantly written article describing the distinct differences between the brains of ME/CFS patients with those of healthy people, in a newly released study from this same research team.

While our primary job as medical science writers is to explain new research accurately, it’s a bonus to know that we captured the patient experience in a compassionate way, and that we have in some way eased their suffering with hope.

Here is a sampling of a few of these letters from around the world:

From British Columbia, Canada:
Thank you for an article that is very well done. I will be printing it for my MD and forwarding it to family and a few close friends because it captures this devastating illness so well. I will keep a copy for myself to remind me (on those dark days) that Dr. Montoya is in my corner.

From Sweden:
I would like to thank you for your very informative and interesting article! This kind of information of what research is going on at Stanford, etc., is very important for us patients with ME all over the world! There is a lot of disinformation coming out about this disease and I therefore very much appreciate your article and especially Dr. Montoya’s passionate engagement with this disease.

From Cali, Colombia:
Here in Cali, Colombia, the city of birth of Dr. Montoya, I feel very happy reading your excellent article, and learning the marvelous and difficult investigation performed by these brilliant scientists. I was moved to tears. Thank you.

From the San Francisco Bay Area:
I want to thank you very much for the powerful piece you wrote about ME/CFS. You tell the story in a very engaging way, which is so compelling. It’s not the usual doom/gloom/dark room story which my daughter and I have encountered frequently in what people write about ME/CFS. Family and friends with whom I have shared the article are appreciative of your writing so descriptively and articulately about all aspects of ME/CFS: the science, the inequity of research funding, the personal experience of a patient, the work of Drs. Montoya/Mark Davis/Holden Maecker.

From India:
Today I have gone through your article about Erin’s story. How she recovered from CFS had given me a ray of hope as I am also suffering from such an ailment for the last 6-8 years.

From Atlanta, Georgia:
I just read your beautifully written article on Immune System Disruption. First soccer caught my eye, then “swimming in the primordial soup of creative disruption” locked me in. I read every word … and I am going to spend the rest of the night in Atlanta copying [my internal medicine doctor] on the article.

From Australia:
Just wanted to thank you for your excellent article. It could really make a difference in raising awareness and I appreciate the quality of your writing. I have suffered from CFS/ME for many years in Australia and find the research project and your understanding very encouraging.

From the blogosphere:
I just wanted to thank you for taking the time to write such an in-depth, accurate article on our oft-ignored illness. Dr. Montoya is a hero within the ME/CFS community, but I didn’t know about the others at Stanford also working on ME/CFS — that gives me some hope for a better future! I plan to share your article on my ME/CFS blog and in several Facebook groups for ME/CFS that I belong to.

Previously: Some headway on chronic fatigue syndrome: Brain abnormalities pinpointedUnbroken: A chronic-fatigue patient’s long road to recovery, Deciphering the puzzle of chronic-fatigue syndrome and Stanford Medicine magazine traverses the immune system
Image, showing white matter differences between a ME/CFS patient sample an a healthy control, by Michael Zeineh/Stanford

Biomed Bites, Immunology, Infectious Disease, Research, Stanford News

Figuring out a parasite’s secrets – insights from studying Toxoplasma gondii

Figuring out a parasite's secrets - insights from studying Toxoplasma gondii

Welcome to Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of disciplines. 

You’ve probably heard that pregnant women shouldn’t get near the litter box. The reason is that many kitties carry a parasite called Toxoplasma gondii, which is transmitted through their feces. The parasite infects about 2 billion people worldwide, according to Stanford microbiologist John Boothroyd, PhD.

Boothroyd, who also serves as the associate vice provost for graduate education, directs a lab that has uncovered some of the basic biology of this single-celled protozoan parasite. Here’s Boothroyd in the video above:

Most of the time, this causes no significant disease, very few symptoms and probably something that most of these people will never know they were infected with. Occasionally, however, this parasite can cause devastating disease. It can affect the brain of the unborn child, it can cause severe neurological problems, it can even kill the developing fetus.

Toxoplasmosis, or infection with the parasite, can also cause serious complications in immunocompromised individuals. Boothroyd said he was drawn to the study of the T. gondii because it is clinically significant — he has the opportunity to help millions of people: “I wanted something where I felt the work we were doing was worth the many, many hours that I and the people I worked with put in to the daily effort.” T. gondii is also related to the Plasmodium parasites that cause malaria and some of the work from Boothroyd’s lab has been translated into insights into malaria.

Boothroyd’s team also identified the T. gondii protein that triggers the immune response in humans. With that knowledge, the investigators were able to insert the gene coding for that protein into yeast, letting the yeast produce the protein, “instead of having to grow the parasite in literally hundreds of thousands of mice a year and then killing those mice to get the parasite,” Boothroyd said. He went on to explain:

The situation in which Toxoplasma presents the most significant problem for the doctor and for the patient is in the pregnant woman. The challenge becomes first, is she infected, and if so, has the parasite crossed the placenta and reached the fetus. And third, what is the consequence of the infection in the fetus? All three of those we have addressed through our work.

Although much about the parasitic diseases remains unknown, Boothroyd is glad he picked T. gondii to focus on: “I think we’ve been able to do some real good with this work.”

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

Previously: Stanford microbiologist’s secret sauce for disease detection, Cat guts, car crashes and warp-speed Toxoplasma infections and Patrick House discusses Toxoplasma gondii, parasitic mind control and zombies

Aging, Neuroscience, Research

Being bilingual “provides the brain built-in exercise”

Being bilingual "provides the brain built-in exercise"

Spanish_booksWith less than two months left in 2014, many of us will soon begin the annual ritual of selecting our New Year’s resolutions. Those who are looking to boost their brain power may want to consider learning a second language in 2015: Research published today in the journal Brain and Language shows that being bilingual makes the brain more efficient at processing information.

In the study, researchers used functional magnetic resonance imaging (fMRI) technology to examine participants’ brains as they performed language comprehension tests. For example, researchers would say the word “cloud” to individuals while showing them four pictures, including one of a cloud and others of similar-sounding objects, like a clown. To complete the exercise, participants had to recognize the correct photo and ignore the irrelevant images. According to a release, study results showed:

The bilingual speakers were better at filtering out the competing words because their brains are used to controlling two languages and inhibiting the irrelevant words, the researchers found.

The fMRI scans showed that “monolinguals had more activation in the inhibitory control regions than bilinguals; they had to work much harder to perform the task,” [said lead author Viorica Marian, PhD.]

“Inhibitory control is a hallmark of cognition,” said Marian. “Whether we’re driving or performing surgery, it’s important to focus on what really matters and ignore what doesn’t.”

The fact that bilinguals are constantly practicing inhibitory control could also help explain why bilingualism appears to offer a protective advantage against Alzheimer’s and dementia, said Marian.

“That’s the exciting part,” she said. “Using another language provides the brain built-in exercise. You don’t have to go out of your way to do a puzzle because the brain is already constantly juggling two languages.”

The findings add to the growing body of scientific evidence showing that being bilingual can have profound impacts on your brain.

Previously: Study shows bilingualism may enhance attention and working memory and ¿Habla Español? How bilingualism may delay the onset of Alzheimer’s symptoms
Photo by Megan Morris

Mental Health, Public Health, Research

Survey shows nearly a quarter of U.S. workers have been diagnosed with depression in their lifetime

Survey shows nearly a quarter of U.S. workers have been diagnosed with depression in their lifetime

4369627924_ccd7f6f7ff_zDepression is a major contributor to absenteeism, reduced productivity and disability among adults in the United States. Now results from a survey examining the societal and economic burden of depression in the workplace show that almost a quarter of employees have been diagnosed with depression in their lifetime and that two in five patients have missed work, for an average of 10 day per year, because of it.

The findings underscore the importance of decreasing the stigma associated with mental-health conditions in the workplace and providing workers with support services and resources. According to a release, additional results also showed:

…64 percent of survey participants reported cognitive-related challenges, as defined by difficulty concentrating, indecisiveness and/or forgetfulness, have the most impact on their ability to perform tasks at work as normal. Presenteeism (being at work, but not engaged/productive) has been found to be exacerbated by these challenges related to thinking on the job.

Despite how depression is affecting our workforce, 58 percent of employees surveyed who have been diagnosed with depression indicate they had not told their employer of their disease. In addition, 49 percent felt telling their employer would put their job a risk and, given the economic climate, 24 percent felt it was too risky to share their diagnosis with their employer.

These figures directly contribute to the estimated $100 billion annually spent on depression costs by U.S. employers including $44 billion a year in lost productivity alone.

The survey was commissioned by Ohio-based Employers Health and conducted by market research company Ipsos MORI. Questions were asked via an online panel of 1,000 adults, aged 16-64, who have been workers or managers within the last year. Responses were weighted to ensure the sample was representative of this profile. Funding was provided by international pharmaceutical company H. Lundbeck A/S.

Previously: Anxiety shown to be important risk factor for workplace absence, Research shows working out may benefit work life and How work stress affects wellness, health-care costs
Photo by Ryan Hyde

Events, In the News, Research, Science, Stanford News

Breaking through scientific barriers: Stanford hosts 2015 Breakthrough Prize winners

Breaking through scientific barriers: Stanford hosts 2015 Breakthrough Prize winners

6018618935_38997291a8_zYoung scientists, I have good news: Nearly all of the 2015 winners of the Breakthrough Prize in Life Sciences pledged to devote at least some of their new-found riches to education programs that encourage budding scientists. No details yet, as the prizes were less than a day old when the researchers announced their plans at the Breakthrough Prize Life Sciences Symposium hosted by Stanford  yesterday.

“The Breakthrough Prize winners have done such amazing things,” said Lloyd Minor, MD, dean of the School of Medicine. Minor lauded the  founders of the award, Silicon Valley luminaries Sergey Brin and Anne Wojcicki, Jack Ma and Cathy Zhang, Yuri and Julia Milner, and Mark Zuckerberg and Priscilla Chan. “They have put together this wonderful way of rewarding and awarding scientists for the work they are doing. It’s a real privilege for us at Stanford to host the symposium.”

The six scientists, who each won a $3 million award, fielded questions and let the audience in on a secret: the path toward scientific success wasn’t always easy.

“I would have never, ever in a million years have predicted I would have been sitting up here,” said C. David Allis, PhD, a professor at The Rockefeller University who was honored for his discoveries in chromatin biology, or the study of the proteins associated with DNA. Chromatin was once thought to be useless and Allis said he received plenty of criticism about his research focus.

Jennifer Doudna, PhD, a professor of molecular and cell biology and chemistry at UC Berkeley, said she didn’t know any scientists growing up in Hawaii. It wasn’t until a cancer researcher visited her high school, giving Doudna her first glimpse at her future career. Doudna, who is also affiliated with the Howard Hughes Medical Institute and the Lawrence Berkeley National Lab, won along with microbiologist Emmanuelle Charpentier, PhD, for their work on genome editing. Charpentier leads the department of regulation in infection biology at the Helmholtz Centre for Infection Research in Germany.

Gary Ruvkun, PhD, said that although he’s a professor of genetics at Harvard Medical School and the Massachusetts General Hospital, he still hasn’t mastered the art of mentoring. “I’ve had people in my lab refer to me as the least grown up,” he said.  Ruvkun was recognized — along with molecular biologist Victor Ambros, PhD, of the University of Massachusetts Medical School — for their work on microRNAs, small pieces of RNA that regulate gene expression.

All of the winners thanked their family, mentors, colleagues, but Alim Louis Benabid, MD, PhD, thanked his patients as well. Benabid, board chairman of the Clinatec Institute in France, said many patients are embarrassed when their doctor asks them to take off their clothes. His patients let him stick his fingers in their brains, he joked. Benabid was honored for demonstrating that deep brain stimulation can alleviate some symptoms of Parkinson’s disease.

In the full-day symposium, several former Breakthrough Prize winners spoke, and Bay Area graduate students and postdocs hosted a poster session.

Previously: Are big-money science prizes a good thing?, Funding basic science leads to clinical discoveries, eventually and Why basic research is the venture capital of the biomedical world
Photo by Petras Gagilas

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