Published by
Stanford Medicine

Category

NIH

Genetics, NIH, Research, Videos

DNA origami: How our genomes fold

DNA origami: How our genomes fold

Here’s an interesting factoid about our genomes: If you stretched out the DNA in a single cell, which is only a few millionths of an inch wide, it would span more than six feet. And another: DNA folding is a dynamic process that changes over time. Scientists have been trying to understand how DNA folds itself up so efficiently, and a recent post on the NIH Director’s Blog highlights new research illustrating how the human genome folds inside the cell’s nucleus, as well as how DNA folding affects gene regulation. The research team created this delightful video that demonstrates the principles involved using origami art.

Researchers have been working to determine how cells regulate gene expression for nearly as long as we’ve known about DNA. How, for example, do nerve cells know to turn off only nerve cell genes and turn off bone cell genes? DNA folding loops are part of the answer. This research team, which published their findings in a paper in Cell yesterday, found that the number of loops is much lower than expected. There are only 10,000 loops instead of the predicted millions, and they form on/off switches in DNA. As explained in the blog post:

[The] paper in Cell adds fascinating details to that map, and it confirms that DNA loops appear to play a crucial role in gene regulation. The researchers found that many stretches of DNA with the potential to fold into loops have genes located at one end and, at the other end, novel genetic switches. When a loop forms, placing a hidden switch in contact with a once-distant gene, the gene is turned on or off. In fact, the mapping work uncovered thousands of these “secret” switches within the genome—information that may provide valuable new clues for understanding cancer and many other complex, common diseases.

Previously: DNA architecture fascinates Stanford researcher – and dictates biological outcomes

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.

Continue Reading »

Aging, NIH, Public Health, Research, Science, Stanford News

Tick tock goes the clock – is aging the biggest illness of all?

Tick tock goes the clock - is aging the biggest illness of all?

3821120232_d1452b4109_zIt’s an uncomfortable truth that aging is the single biggest risk factor for many chronic diseases. It’s also completely out of our control. (The alternative is, well, not so fun to contemplate.) But although we all think we’d like to live longer, longevity in and of itself is not necessarily a good thing. Living longer rapidly loses its appeal if you’re too sick or feeble to really enjoy your extra “golden” years.

But researchers from many scientific disciplines are now working to understand how and why our bodies tend to break down as time passes. The Trans-NIH Geroscience Interest Group (a group of researchers from numerous NIH institutes) interested in aging held a summit in 2013 to explore mechanisms of aging and identify common themes that could serve as research targets. The thought is that understanding, and slowing, aging may be an efficient way to tackle many chronic diseases simultaneously.

Now the group, which includes Stanford geneticist Anne Brunet, PhD; neurologist Tony Wyss-Coray, PhD; and Thomas Rando, MD, PhD, has released the conclusions of the summit and outlined a plan for the work that lies ahead. (Rando is the director of the Glenn Center for the Biology of Aging at Stanford.) Many of the findings focus  on a concept called “healthspan,” which designates the portion of a person’s lifespan in which he or she is relatively healthy and fully functional. From the Cell article:

While life expectancy continues to rise, healthspan is not keeping pace because current disease treatment often decreases mortality without preventing or reversing the decline in overall health.  Elders are sick longer, often coping with multiple chronic diseases simultaneously.  Thus, there is an urgent need to extend healthspan.

The researchers identified seven intertwined “pillars of aging” for targeted research, including adaptation to stress, stem cells and regeneration, metabolism, macromolecular damage, inflammation, epigenetics and a concept called proteostasis, which describes the intricate dance in which proteins are made, transported and degraded within a cell. They suggest the creation of an Aging Research Initiative that works to merge the emerging field of geroscience with research on chronic disease and to search for therapeutic interventions that could extend both lifespan and healthspan.

Continue Reading »

Clinical Trials, Health Policy, NIH, Women's Health

A look at NIH’s new rules for gender balance in biomedical studies

A look at NIH’s new rules for gender balance in biomedical studies

In May, Francis Collins, MD, PhD, director of the National Institutes of Health, co-authored a Comment piece in Nature, outlining new requirements for biomedical researchers that made balancing the sex of animals and cell lines in studies much more important than they have been in the past. The first changes were set to be implemented this month. But, as Scientific American reported earlier this week,  the NIH isn’t likely to implement the changes as quickly as previously thought:

Funding rules, however, have yet to change, with only one week left in the month. Instead, the agency is gathering comments from researchers about which research areas need sex balance the most and the challenges scientists face in including male and female subjects in their studies. Officials have set aside $10.1 million in grants for scientists who want to add animals of the opposite sex to their existing experiments. The NIH is also making videos and online tutorials to teach scientists who are new to studying both sexes how to design such studies. Meanwhile, [Janine A. Clayton, director of the NIH’s Office of Research on Women’s Health] “can’t say” when new funding rules will take effect. “Details about the policy and implementation plans will roll out during the next year,” she says.

Scientists rely heavily on male animals, rarely using females, and the changes would require some drastic changes for researchers seeking funds from NIH. More from Scientific American:

Once in place and codified, the requirement would be a major shift for the nation’s biomedical labs, many of which study mostly or exclusively male animals. One estimate found that pharmacology studies include five times as many male animals as female ones, while neuroscience studies are skewed 5.5:1 male-to-female.

Scientists assumed biology findings that held in males would apply just as well to females, but a growing body of research has discovered this is not always true. Female and male mice’s bodies make different amounts of many proteins, for example. Men and women have differing risks for many health conditions that are not obviously sex-based, including anxiety, depression, hypertension and strokes. Yet those diseases are still predominantly studied in male animals. Scientists who study sex differences think the mismatch might be the reason women suffer more side effects than men do from drugs approved by the U.S. Food and Drug Administration. Pharmaceuticals that researchers test mainly on male animals may work better for men than for women.

When the NIH does begin to implement these changes, the first steps will be training staff and grantees on what these changes mean for experimental design. And it should be noted that this isn’t the first time that NIH has encouraged sex balance. In 2013, its Office of Research on Women’s Health started a program of supplemental grants for currently funded researchers to add enough animals for gender-balanced study results.

Previously: Why it’s critical to study the impact of gender differences on diseases and treatments, Large federal analysis: Hormone therapy shouldn’t be used for chronic-disease prevention and A call to advance research on women’s health issues
Photo by Mycroyance

NIH, Research, Science Policy, Stanford News

Shake up research rewards to improve accuracy, says Stanford's John Ioannidis

Shake up research rewards to improve accuracy, says Stanford's John Ioannidis

currencyLab animals such as mice and rats can be trained to press a particular lever or to exhibit a certain behavior to get a coveted food treat. Ironically the research scientists who carefully record the animals’ behavior really aren’t all that different. Like mice in a maze, researchers in this country are rewarded for specific achievements, such as authoring highly cited papers in big name journals or overseeing large labs pursuing multiple projects. These rewards come in the form of promotions, government grants and prestige among a researcher’s peers.

Unfortunately, the achievements do little to ensure that the resulting research findings are accurate. Stanford study-design expert John Ioannidis, MD, DSci, has repeatedly pointed out serious flaws in much published research (in 2005 he published what was to be one of the most highly-accessed and most highly-cited papers ever in the biomedical field “Why most published research findings are false”).”

Today, Ioannidis published another paper in PLoS Medicine titled “How to make more published research true.” He explores many topics that could be addressed to improve the reproducibility and accuracy of research. But the section that I found most interesting was one in which he argues for innovative, perhaps even disruptive changes to the scientific reward system. He writes:

 The current system does not reward replication—it often even penalizes people who want to rigorously replicate previous work, and it pushes investigators to claim that their work is highly novel and significant. Sharing (data, protocols, analysis codes, etc.) is not incentivized or requested, with some notable exceptions. With lack of supportive resources and with competition (‘‘competitors will steal my data, my ideas, and eventually my funding”) sharing becomes even disincentivized. Other aspects of scientific citizenship, such as high-quality peer review, are not valued.

Instead he proposes a system in which simply publishing a paper has no merit unless the study’s findings are subsequently replicated by other groups. If the results of the paper are successfully translated into clinical applications that benefit patients, additional “currency” units would be awarded. (In the example of the mice in the maze, the currency would be given in the form of yummy food pellets. For researchers, it would be the tangible and intangible benefits accrued by those considered to be successful researchers). In contrast, the publication of a paper that was subsequently refuted or retracted would result in a reduction of currency units for the authors. Peer review and contributions to the training and education of others would also be rewarded.

The concept is really intriguing, and some ideas would really turn the research enterprise in this country on its head. What if a researcher were penalized (fewer pellets for you!) for achieving an administrative position of power… UNLESS he or she also increased the flow of reliable, reproducible research? As described in the manuscript:

[In this case] obtaining grants, awards, or other powers are considered negatively unless one delivers more good-quality science in proportion. Resources and power are seen as opportunities, and researchers need to match their output to the opportunities that they have been offered—the more opportunities, the more the expected (replicated and, hopefully, even translated) output. Academic ranks have no value in this model and may even be eliminated: researchers simply have to maintain a non-negative balance of output versus opportunities. In this deliberately provocative scenario, investigators would be loath to obtain grants or become powerful (in the current sense), because this would be seen as a burden. The potential side effects might be to discourage ambitious grant applications and leadership.

Ioannidis, who co-directs with Steven Goodman, MD, MHS, PhD, the new  Meta-Research Innovation Center at Stanford, or METRICS, is quick to acknowledge that these types of changes would take time, and that the side effects of at least some of them would likely make them impractical or even harmful to the research process. But, he argues, this type of radical thinking might be just what’s needed to shake up the status quo and allow new, useful ideas to rise to the surface.

Previously: Scientists preferentially cite successful studies, new research shows, Re-analyses of clinical trial results rare, but necessary, say Stanford researchers  and John Ioannidis discusses the popularity of his paper examining the reliability of scientific research
Photo by Images Money

History, Medicine and Society, NIH, Public Health

"Don't go to bed with a malaria mosquito:" exploring World War II medical posters

"Don't go to bed with a malaria mosquito:" exploring World War II medical posters

After exploring Stanford’s collection of historical medical images last week after a tour of the School of Medicine, I got hooked. Hooked on historical medical images — a quirky interest tailor-made for the internet. Turns out the National Institutes of Health’s U.S. National Library of Medicine maintains a massive image library, one that includes some fabulous propaganda posters from World War II, including the lady mosquito with the alluring proboscis (above).

Others in the World War II poster collection focus on venereal diseases, recruiting nurses and doctors, encouraging blood donations and even curbing noise or visiting the dentist.

And that’s just World War II posters. Its Flickr collection is tantalizing, kicking off with a series of medical oddities reminiscent of Philadelphia’s Mütter Museum. It’s quite addictive – just warning you.

Previously: A trip down memory lane: Stories from the early days of the School of Medicine, #ACT4NIH seeks stories to spur research investment and Examining the impact of psychological distress on soldiers’ spinal injuries
Images courtesy of U.S National Library of Medicine

Big data, Bioengineering, NIH, Research, Science Policy, Stanford News

$23 million in NIH grants to Stanford for two new big-data-crunching biomedical centers

$23 million in NIH grants to Stanford for two new big-data-crunching biomedical centers

More than $23 million in grants from the National Institutes of Health – courtesy of the NIH’s Big Data to Knowledge (BD2K) initiative – have launched two Stanford-housed centers of excellence bent on enhancing scientists’ capacity to compare, contrast and combine study results in order to draw more accurate conclusions, develop superior medical therapies and understand human behaviors.

Huge volumes of biomedical data – some of it from carefully controlled laboratory studies, increasing amounts of it in the form of electronic health records, and a building torrent of data from wearable sensors – languish in isolated locations and, even when researchers can get their hands on them, are about as comparable as oranges and orangutans. These gigantic banks of data, all too often, go unused or at least underused.

But maybe not for long. “The proliferation of devices monitoring human activity, including mobile phones and an ever-growing array of wearable sensors, is generating unprecedented quantities of data describing human movement, behaviors and health,” says movement-disorders expert Scott Delp, PhD, director of the new National Center for Mobility Data Integration to Insight, also known as the Mobilize Center. “With the insights gained from subjecting these massive amounts of data to  state-of-the-art analytical techniques, we hope to enhance mobility across a broad segment of the population,” Delp told me.

Directing the second grant recipient, the Center for Expanded Data and Retrieval (or CEDAR), is Stanford’s Mark Musen, MD, PhD, a world-class biomedical-computation authority. As I wrote in an online story:

[CEDAR] will address the need to standardize descriptions of diverse biomedical laboratory studies and create metadata templates for detailing the content and context of those studies. Metadata consists of descriptions of how, when and by whom a particular set of data was collected; what the study was about; how the data are formatted; and what previous or subsequent studies along similar lines have been undertaken.

The ultimate goal is to concoct a way to translate the banter of oranges and orangutans, artichokes and aardvarks now residing in a global zoo (or is it a garden?) of diverse databases into one big happy family speaking the same universal language, for the benefit of all.

Previously: NIH associate director for data science on the importance of “data to the biomedicine enterprise”, Miniature wireless device aids pain studies and Stanford bioengineers aim to better understand, treat movement disorders

Clinical Trials, Ethics, Genetics, NIH, Pediatrics

The promise and peril of genome sequencing newborns

NICUEven though doctors and researchers have made great strides in caring for patients in the past few decades, there are still many illnesses that are difficult to diagnose, let alone treat. Among the most heartbreaking cases are those newborns who come down with mysterious illnesses that defy medical expertise. But in recent years, doctors have turned to genetic sequencing in some of these cases to identify the culprit causes of the illnesses.

Last year, the National Institutes of Health funded four pilot projects looking into the efficacy and ethics of genetic screening for otherwise inexplicable illnesses in newborns. The first of the trials will begin next week at Children’s Mercy Hospital in Kansas City, Missouri, as reported in a recent story from Nature. The trial at Children’s Mercy Hospital will focus on rapid genome sequencing with a 24-hour turn-around. Genetic sequencing normally takes weeks, but some of these infants don’t survive that long. Doctors have used similar rapid genome sequencing to diagnose an infant with cardiac defects at Lucile Packard Children’s Hospital Stanford.

Earlier this year, I had the opportunity to report on a rare genetic mutation that leads young infants to develop inflammatory bowel disease. I spoke with some parents of children with the mutation, which was identified by sequencing the children’s exome – just the protein-producing part of the genome – as part of a new project (separate from the NIH trials) at the University of Toronto in Canada. As I explain in the piece, getting a bone marrow transplant early enough can help alleviate symptoms and save the child’s life.

The parents were uniformly grateful for the sequencing technology that made it possible to understand what was causing their baby’s illness, even in cases where the child didn’t survive long after diagnosis. One mother mentioned that realizing some of the best doctors in the country didn’t know what was ailing her daughter made the experience even more frightening. After months of worried confusion about their young children’s deteriorating health, for these parents to have an answer was a relief.

But because the technique is so new, several ethical details still need clarification – which the NIH study hopes to answer. From the Nature news story:

Misha Angrist, a genomic-policy expert at Duke University in Durham, North Carolina, says that although the 24-hour genome process is impressive, it is not clear whether genomic sequencing of newborns will soon become standard practice. Many questions remain about who will pay for sequencing, who should have access to the data and how far clinicians should go in extracting genome information that is unrelated to the disease at hand. Then there is the question of how informative the process is. “I think it’s really important that we do these experiments so that we start to see what that yield is,” Angrist says.

All four teams will include an ethicist who will be responsible for dealing with questions like the ones Angrist raises. The other three trials at Boston Children’s Hospital, the University of North Carolina in Chapel Hill, and at the University of California, San Francisco are still awaiting approval from the Federal Drug Adminstration.

Previously: Stanford patient on having her genome sequenced: “This is the right thing to do for our family” When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside Whole genome sequencing: The known knowns and the unknown unknowns
Photo by kqedquest

Neuroscience, NIH, Research, Stanford News

Federal BRAIN Initiative funds go to create better sensors for recording the brain's activity

Federal BRAIN Initiative funds go to create better sensors for recording the brain's activity

Optical voltage sensorUpdated 10-2-14: A quote from Schnitzer was added to the post.

***

10-1-14: Yesterday the National Institutes of Health handed out the first $46 million in funding for the BRAIN Initiative, announced in 2013. Stanford got one of those awards, worth almost $1 million to develop improved ways of recording activity in the brain.

The award went to applied physicist Mark Schnitzer, PhD, and bioengineer Michael Lin, MD, PhD, to expand on work they published last year. The pair had each developed tiny sensors that could detect voltage changes within a neuron. These provided the first real-time view of a nerve’s activity. When I wrote about their initial work earlier this year I described how these probes could be used:

With these tools scientists can study how we learn, remember, navigate or any other activity that requires networks of nerves working together. The tools can also help scientists understand what happens when those processes don’t work properly, as in Alzheimer’s or Parkinson’s diseases, or other disorders of the brain.

The proteins could also be inserted in neurons in a lab dish. Scientists developing drugs, for example, could expose human nerves in a dish to a drug and watch in real time to see if the drug changes the way the nerve fires. If those neurons in the dish represent a disease, like Parkinson’s disease, a scientist could look for drugs that cause those cells to fire more normally.

The BRAIN initiative award will help the team develop better sensors, and also improve the technology for recording the signals. In a conversation, Lin told me that a brain signal lasts about 2-4 milliseconds. Any camera for recording that activity needs to record about 1,000 frames per second, and current cameras operate at about one tenth of that speed. Schnitzer has expertise in developing tiny cameras for recording biological activity and will be working to create a faster camera to pair with Lin’s improved sensors.

Schnitzer participated in a panel discussion at a White House Brain Conference held the same day the grants were announced. He said, “I think there are many important roles for engineering and new technology that will likely emerge in the BRAIN initiative… I expect the results will be profound by helping to unlock some of the central mysteries of brain function, by providing new tools and helping to lay the basis for conceptual foundations in our efforts to prevent and cure brain disease and brain disorders and also in harnessing some of the brain’s computational strategies for humanity’s own technological purposes.”

Previously: Thoughts light up with new Stanford-designed tool for studying the brainBold and game-changing” federal report calls for $4.5 billion in brain-research fundingNIH announces focus of funding for BRAIN initiative and New tool for reading brain activity of mice could advance study of neurodegenerative diseases
Image courtesy of Michael Lin

Cancer, Clinical Trials, In the News, NIH, Patient Care, Research

National Cancer Institute looking for "Exceptional Responders"

OLYMPUS DIGITAL CAMERAHope is a powerful force in cancer treatment. For patients and their families, the hope is that, no matter how unlikely, the treatment plan will cure the patient and eradicate the disease. Sadly, this is sometimes a long shot. But sometimes, against all odds, the therapy is unusually successful. Now the National Cancer Institute is trying to learn why.

This week the institute launched a study into the phenomena of “Exceptional Responders” – that is, cancer patients who have a unique response to treatments (primarily chemotherapy) that have not been effective for most other patients. As they describe in a Q&A about the effort:

For this initiative, exceptional responders will be identified among patients enrolled in early-phase clinical trials in which fewer than 10 percent of the patients responded to the treatments being studied; patients who were treated with drugs not found to be generally effective for their disease; patients who were treated in later-phase clinical trials of single agents or combinations; and even patients who were treated with established therapies. In this pilot study, malignant tissue (and normal tissue, when possible) and clinical data will be obtained from a group of exceptional responders and analyzed in detail. The goal is to determine whether certain molecular features of the malignant tissue can predict responses to the same or similar drugs.

The researchers would like to obtain tumor samples, as well as normal tissue, from about 100 exceptional responders. They’ll compare DNA sequences and RNA transcript levels and other molecular measurements to try to understand why these patients were such outliers in their response to treatment. In at least one previous case, an exceptional responder with bladder cancer led researchers to discover a new molecular pathway involved in the development of the disease, and suggested new therapeutic approaches for other similar patients.

Do you know someone who might qualify for the study? More from the Q&A:

Patients who believe they may be exceptional responders should contact their physicians or clinical trialists to see if they can assist in submitting tissue for consideration. […] Investigators who have tissue from a potential exceptional responder should send an email to NCIExceptionalResponders@mail.nih.gov. The email should include a short description of the case, without patient identifiers; information about whether tissue collected before the exceptional response is available; whether informed consent was given to use tissue for research; and the patient’s vital status.

Photo by pol sifter

Stanford Medicine Resources: