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Dr. Francis Collins

Announcing the HEALing Communities Awards

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HEALing Communities press conference
Along with (left to right) Assistant Secretary for Mental Health and Substance Use Elinore McCance-Katz, Health and Human Services Secretary Alex Azar, and Assistant Secretary for Health Brett Giroir; I was pleased to take part in a news conference on April 18, 2019 to announce the awardees for our HEALing Communities Study. The study will aim to reduce opioid overdose deaths dramatically in some of our nation’s hardest-hit communities. Credit: HHS

Looking for Answers to Epilepsy in a Blood Test

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Gemma Carvill and lab members
Gemma Carvill (second from right) with members of her lab. Courtesy of Gemma Carvill

Millions of people take medications each day for epilepsy, a diverse group of disorders characterized by seizures. But, for about a third of people with epilepsy, current drug treatments don’t work very well. What’s more, the medications are designed to treat symptoms of these disorders, basically by suppressing seizure activity. The medications don’t really change the underlying causes, which are wired deep within the brain.

Gemma Carvill, a researcher at Northwestern University Feinberg School of Medicine, Chicago, wants to help change that in the years ahead. She’s dedicated her research career to discovering the genetic causes of epilepsy in hopes of one day designing treatments that can control or even cure some forms of the disorder [1].

It certainly won’t be easy. A recent paper put the number of known genes associated with epilepsy at close to 1,000 [2]. However, because some disease-causing genetic variants may arise during development, and therefore occur only within the brain, it’s possible that additional genetic causes of epilepsy are still waiting to be discovered within the billions of cells and their trillions of interconnections.

To find these new leads, Carvill won’t have to rely only on biopsies of brain tissue. She’s received a 2018 NIH Director’s New Innovator Award in search of answers hidden within “liquid biopsies”—tiny fragments of DNA that research in other forms of brain injury and neurological disease [3] suggests may spill into the bloodstream and cerebrospinal fluid (CSF) from dying neurons or other brain cells following a seizure.

Carvill and team will start with mouse models of epilepsy to test whether it’s possible to detect DNA fragments from the brain in bodily fluids after a seizure. They’ll also attempt to show DNA fragments carry telltale signatures indicating from which cells and tissues in the brain those molecules originate. The hope is these initial studies will also tell them the best time after a seizure to collect blood samples.

In people, Carvill’s team will collect the DNA fragments and begin searching for genetic alterations to explain the seizures, capitalizing on Carvill’s considerable expertise in the use of next generation DNA sequencing technology for ferreting out disease-causing variants. Importantly, if this innovative work in epilepsy pans out, it also can be applied to any other neurological condition in which DNA spills from dying brain cells, including Alzheimer’s disease and Parkinson’s disease.

References:

[1] Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. Calhoun JD, Carvill GL. J Neurogenet. 2018 Sep 24:1-18.

[2] Epilepsy-associated genes. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP. Seizure. 2017 Jan;44:11-20.

[3] Identification of tissue-specific cell death using methylation patterns of circulating DNA. Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A, Rubertsson S, Nellgård B, Blennow K, Zetterberg H, Spalding K, Haller MJ, Wasserfall CH, Schatz DA, Greenbaum CJ, Dorrell C, Grompe M, Zick A, Hubert A, Maoz M, Fendrich V, Bartsch DK, Golan T, Ben Sasson SA, Zamir G, Razin A, Cedar H, Shapiro AM, Glaser B, Shemer R, Dor Y. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1826-34.

Links:

Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Gemma Carvill Lab (Northwestern University Feinberg School of Medicine, Chicago)

Carvill Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke


Study Finds No Benefit for Dietary Supplements

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Eating healthy
Credit: iStock/Artfully79

More than half of U.S. adults take dietary supplements [1]. I don’t, but some of my family members do. But does popping all of these vitamins, minerals, and other substances really lead to a longer, healthier life? A new nationwide study suggests it doesn’t.

Based on an analysis of survey data gathered from more than 27,000 people over a six-year period, the NIH-funded study found that individuals who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to food consumption.

The study, published in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess [2]. For instance, people who took more than 1,000 milligrams of supplemental calcium per day were more likely to die of cancer than those who didn’t.

The researchers, led by Fang Fang Zhang, Tufts University, Boston, were intrigued that so many people take dietary supplements, despite questions about their health benefits. While the overall evidence had suggested no benefits or harms, results of a limited number of studies had suggested that high doses of certain supplements could be harmful in some cases.

To take a broader look, Zhang’s team took advantage of survey data from tens of thousands of U.S. adults, age 20 or older, who had participated in six annual cycles of the National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010. NHANES participants were asked whether they’d used any dietary supplements in the previous 30 days. Those who answered yes were then asked to provide further details on the specific product(s) and how long and often they’d taken them.

Just over half of participants reported use of dietary supplements in the previous 30 days. Nearly 40 percent reported use of multivitamins containing three or more vitamins.

Nutrient intake from foods was also assessed. Each year, the study’s participants were asked to recall what they’d eaten over the last 24 hours. The researchers then used that information to calculate participants’ nutrient intake from food. Those calculations indicated that more than half of the study’s participants had inadequate intake of vitamins D, E, and K, as well as choline and potassium.

Over the course of the study, more than 3,600 of the study’s participants died. Those deaths included 945 attributed to cardiovascular disease and 805 attributed to cancer. The next step was to look for any association between the nutrient intake and the mortality data.

The researchers found the use of dietary supplements had no influence on mortality. People with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were less likely to die. However, that relationship only held for nutrient intake from food consumption.

People who reported taking more than 1,000 milligrams of calcium per day were more likely to die of cancer. There was also evidence that people who took supplemental vitamin D at a dose exceeding 10 micrograms (400 IU) per day without a vitamin D deficiency were more likely to die from cancer.

It’s worth noting that the researchers did initially see an association between the use of dietary supplements and a lower risk of death due to all causes. However, those associations vanished when they accounted for other potentially confounding factors.

For example, study participants who reported taking dietary supplements generally had a higher level of education and income. They also tended to enjoy a healthier lifestyle. They ate more nutritious food, were less likely to smoke or drink alcohol, and exercised more. So, it appears that people who take dietary supplements are likely to live a longer and healthier life for reasons that are unrelated to their supplement use.

While the study has some limitations, including the difficulty in distinguishing association from causation, and a reliance on self-reported data, its findings suggest that the regular use of dietary supplements should not be recommended for the general U.S. population. Of course, this doesn’t rule out the possibility that certain subgroups of people, including perhaps those following certain special diets or with known nutritional deficiencies, may benefit.

These findings serve up a reminder that dietary supplements are no substitute for other evidence-based approaches to health maintenance and eating nutritious food. Right now, the best way to live a long and healthy life is to follow the good advice offered by the rigorous and highly objective reviews provided by the U.S. Preventive Services Task Force [3]. Those tend to align with what I hope your parents offered: eat a balanced diet, including plenty of fruits, veggies, and healthy sources of calcium and protein. Don’t smoke. Use alcohol in moderation. Avoid recreational drugs. Get plenty of exercise.

References:

[1] Trends in Dietary Supplement Use Among US Adults From 1999-2012. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. JAMA. 2016 Oct 11;316(14):1464-1474.

[2] Association among dietary supplement use, nutrient intake, and mortality among U.S. adults. Chen F, Du M, Blumberg JB, Ho Chui KK, Ruan M, Rogers G, Shan Z, Zeng L, Zhang. Ann Intern Med. 2019 Apr 9. [Epub ahead of print].

[3] Vitamin Supplementation to Prevent Cancer and CVD: Preventive Medication. U.S. Preventive Services Task Force, February 2014.

Links:

Office of Dietary Supplements (NIH)

Healthy Eating Plan (National Heart, Lung, and Blood Institute/NIH)

National Health and Nutrition Examination Survey (Centers for Disease Control and Prevention, Atlanta)

U.S. Preventive Services Task Force (Rockville, MD)

Fang Fang Zhang (Tufts University, Boston)

NIH Support: National Institute on Minority Health and Health Disparities


An Indisposable Idea from a Disposable Diaper

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3D Silver Nanostructures
Caption: 3D silver nanostructures created using implosion fabrication. Credit: Daniel Oran, Massachusetts Institute of Technology

Using a screwdriver on the tiny microcircuits arrayed inside a computer hard drive can be a real eye strain. Even more challenging is building the microcircuits or other electronic components at the nanoscale, one-billionth of a meter or less.

That’s why researchers are always on the lookout for new tools to help them work on such a minute scale. But some of these incredibly tiny tools and scaffolds can derive from very unexpected sources.

As published in the journal Science, an NIH-funded team has developed a technique called implosion fabrication to build impressively small and intricate components on the nanoscale [1]. Its secret ingredient: water-swollen gels that you’d find in a baby’s disposable diaper.

A baby’s disposable diaper? If that sounds familiar, my blog highlighted a related technique called expansion microscopy a few years ago that uses water-swollen gels that are generated from a compound used in diapers called sodium polyacrylate.

The previously-reported microscopy technique, from the lab of Edward Boyden, Massachusetts Institute of Technology, Cambridge, embeds biological samples in a fine web of sodium polyacrylate. When water is added, the gel expands, blowing up the specimen to 100 times its original size. This groundbreaking technique, called expansion microscopy, has enabled labs around the world to use conventional microscopes for high-resolution, nanoscale imaging.

In the latest work, Boyden’s team, including co-first authors Daniel Oran and Samuel Rodriques, asked a simple question: What would happen if they applied the sample preparation technique used for expansion microscopy—only in reverse?

To find out, Boyden’s team created millimeter-sized blocks of the super-absorbent sodium polyacrylate diaper compound. After using a nifty trick for attaching molecular anchors in a 3D pattern, they dehydrated the gel and voila! The structures imploded and shrank down to one-thousandth their original size, while holding their 3D shape.

During the process, they can add to the anchors a range of functional molecules or elements. These include DNA, nanoparticles, semiconductors, or almost anything that’s needed.

While more work is needed to perfect the new technique, the researchers have already shown it can create objects one cubic millimeter in size, engineered to include intricate details down to about 50 nanometers. For comparison, a virus is about 30 to 50 nanometers.

These latest findings come as a reminder that advances in biomedicine often lead in wonderful and unexpected new directions. Out of the NIH-funded efforts related to The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, members of the Boyden Lab wanted to see the brain better using basic microscopes. Now, we have a widely-applicable promising new approach to nanofabrication.

Reference:

[1] 3D nanofabrication by volumetric deposition and controlled shrinkage of patterned scaffolds. Oran D, Rodriques SG, Gao R, Asano S, Skylar-Scott MA, Chen F, Tillberg PW, Marblestone AH, Boyden ES. Science. 2018 Dec 14;362(6420):1281-1285.

Links:

Size of the Nanoscale (Nano.gov)

Synthetic Neurobiology Group, Ed Boyden (MIT, Cambridge, MA)

The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: Common Fund; National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Human Genome Research Institute; National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke


New Target for Cancer Immunotherapy: Exosomes

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It was once a central tenet of biology that RNA molecules did their work inside the cell. But it’s now clear that RNA molecules are also active outside the cell, with potentially major implications for our health. To learn more about these unrecognized roles, the NIH Common Fund has launched the Extracellular RNA (exRNA) Communication Program.

This month, members of this research consortium described their latest progress in unraveling the secrets of exRNA in a group of 18 papers in the Cell family of journals. And it’s not just RNA that the consortium is studying, it’s also proteins. Among the many exciting results just published is the serendipitous discovery that proteins carried inside tiny, bubble-like vesicles, called exosomes, may influence a cancer’s response to immunotherapy [1]. The work sheds light on why certain cancers are resistant to immunotherapy and points to new strategies for unleashing the immune system in the fight against cancer.

The new findings center on a type of immunotherapy drugs known as checkpoint inhibitors. They are monoclonal antibodies produced by industry that can boost the immune system’s ability to attack and treat cancer.

One of those antibodies specifically targets a protein, called PD-1, on the surface of certain immune cells. When PD-1 binds a similarly named protein, called PD-L1, on the surface of another cell, the interaction prevents immune cells from attacking. Some tumors seem to have learned this and load up on PD-L1 to evade the immune system.

That’s where checkpoint inhibitors come in. By blocking the interaction between PD-1 and PD-L1, the treatment removes a key check on the immune system, allowing certain immune cells to wake up and attack the tumor.

Checkpoint inhibitors work better in some cancer types than in others. In melanoma, for example, up to about 30 percent of patients respond to checkpoint inhibitor therapy. But in prostate cancer, response rates are in the single digits.

Researchers led by Robert Blelloch, a member of the exRNA consortium and a scientist at the University of California, San Francisco, wanted to know why. He and his team looked for clues in RNA within the cells taken from immunotherapy-resistant prostate cancers.

As published in Cell, the researchers got their first hint of something biologically intriguing in an apparent discrepancy in their data. As they expected from prior work, PD-L1 protein was present in the treatment-resistant cancers. But the PD-L1 messenger RNAs (mRNA), which serve as templates for producing the protein, told an unexpected story. The resistant cancer cells made far more PD-L1 mRNAs than needed to produce the modest levels of PD-L1 proteins detected inside the cells.

Where was the missing PD-L1? Blelloch’s team found it in exosomes. The cancer cells were packaging large quantities of the protein inside exosomes and secreting them out of the cell to other parts of the body.

In additional studies with a mouse model of prostate cancer, the researchers found that those PD-L1-packed exosomes travel through the blood and lymphatic systems to lymph nodes, the sites where immune cells become activated. Once there, PD-L1-laden exosomes put the immune system to sleep, preventing certain key cells from locating and attacking the cancer, including the primary tumor and places where it may have spread.

In important follow up studies, the researchers edited two genes in cancer cells to prevent them from producing exosomes. And, in the absence of exosomes, the cells no longer formed tumors. Importantly, both edited and unedited cells still produced PD-L1, but only those that exported PD-L1 in exosomes disarmed the immune system. Studies in a mouse model of immunotherapy-resistant colorectal cancer yielded similar results.

The new evidence suggests that blocking the release of PD-L1 in exosomes, even temporarily, might allow the immune system to launch a successful and sustained attack against a cancer.

Blelloch notes that many intriguing questions remain. For example, it’s not yet clear why antibodies that target PD-L1 on cancer cells don’t disable PD-L1 found in exosomes. The good news is that the new findings suggest it may be possible to find small molecules that do target PD-L1-packed exosomes, unleashing the immune system against cancers that don’t respond to existing checkpoint inhibitors. In fact, Blelloch’s team is already screening for small molecules that might fit the bill.

Since its launch about five years ago, the exRNA Communication Program has published an impressive 480 peer-reviewed papers, including the latest work in the Cell family of journals. I’d encourage readers to click on some of the other excellent work. I hear that another batch of papers will be published later this year.

Reference:

[1] Suppression of exosomal PD-L induces systemic anti-tumor immunity and memory. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R. Cell. 2019 Apr 4;177(2):414-427.

Links:

Video: Unlocking the Mysteries of RNA Communication (Common Fund/NIH)

Immunotherapy to Treat Cancer (National Cancer Institute/NIH)

Blelloch Lab (University of California, San Francisco)

NIH Support: Common Fund; National Cancer Institute; National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse


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