NIH Director's Blog: All items

[Article Digests for Psychology & Social Work]

NIH Director's Blog

 

(https://directorsblog.nih.gov/2024/04/04/fear-switch-in-the-brain-may-point-to-target-for-treating-anxiety-disorders-including-ptsd/) Fear Switch in the Brain May Point to Target for Treating Anxiety Disorders Including PTSD
Apr 4th 2024, 09:00

Researchers found that acute stress switched chemical signals in the brain from producing excitatory glutamate to inhibitory GABA neurotransmitters, and this led to a generalized fear response. Credit: Donny Bliss/NIH, Antonioguillem/Adobe

There’s a good reason you feel fear creep in when you’re walking alone at night in an unfamiliar place or hear a loud and unexpected noise ring out. In those moments, your brain triggers other parts of your nervous system to set a stress response in motion throughout your body. It’s that fear-driven survival response that keeps you alert, ready to fight or flee if the need arises. But when acute anxiety or traumatic events lead to fear that becomes generalized—occurring often and in situations that aren’t threatening—this can lead to debilitating anxiety disorders, including (https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd) post-traumatic stress disorder (PTSD).

Just what happens in the brain’s circuitry to turn a healthy fear response into one that’s harmful hasn’t been well understood. Now, research findings by a team led by (https://biology.ucsd.edu/research/faculty/nspitzer) Nicholas Spitzer and Hui-Quan Li at the University of California San Diego and reported in the journal (https://pubmed.ncbi.nlm.nih.gov/38484078/) Science have pinpointed changes in the biochemistry of the brain and neural circuitry that lead to generalized fear.1 The intriguing findings, from research supported in part by NIH, raise the possibility that it might be possible to prevent or reverse this process with treatments targeting this fear “switch.”

To investigate generalized fear in the brain, the researchers first studied mice in the lab, looking at parts of the brain known to be linked to panic-like fear responses, including an area of the brainstem known as the dorsal raphe. They found that, in the mouse brain, acute stress led to a switch in the chemical messengers, or neurotransmitters, in some neurons within this portion of the mouse brain. Specifically, the chemical signals in the neurons flipped from producing excitatory glutamate neurotransmitters to inhibitory GABA neurotransmitters, and this led to a generalized fear response. They also found that the neurons that had undergone this switch are connected to brain regions that are known to play a role in fear responses including the amygdala and lateral hypothalamus. Interestingly, the researchers also showed they could avert generalized fear responses by preventing the production of GABA in the mouse brain.

To further support their research, the study team then examined postmortem brains of people who had PTSD and confirmed a similar switch in neurotransmitters to what happened in the mice. Next, they wanted to find out if they could block the switch by treating mice with the commonly used antidepressant fluoxetine. They found that when mice were treated with fluoxetine in their drinking water promptly after a stressful event, the neurotransmitter switch and subsequent generalized fear were prevented.

The researchers made even more findings about the timing of the switch that could lead to better treatments. They found that in mice, the switch to generalized fear persisted for four weeks after an acutely stressful event—a period that for the mice may be the equivalent of three years in people. This suggests that treatments may prevent generalized fear and the development of anxiety disorders when given before the brain undergoes a neurotransmitter switch. The findings may also explain why treatment doesn’t seem to be as effective in people who are initially treated for PTSD after having it for a long time.

Going forward, the researchers want to explore targeted approaches to reversing this fear switch after it has taken place. The hope is to discover new ways to rid the brain of generalized fear responses and help treat anxiety disorders including PTSD, a condition which will affect more than six in every 100 people at some point in their lives.2

References:

[1] Li HQ, et al. (https://pubmed.ncbi.nlm.nih.gov/38484078/) Generalized fear after acute stress is caused by change in neuronal cotransmitter identity. Science. DOI: 10.1126/science.adj5996 (2024).[2] (https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd) Post-Traumatic Stress Disorder (PTSD). National Institute of Mental Health.

NIH Support: National Institute of Neurological Disorders and Stroke

(https://directorsblog.nih.gov/2024/03/28/immune-checkpoint-discovery-has-implications-for-treating-cancer-and-autoimmune-diseases/) Immune Checkpoint Discovery Has Implications for Treating Cancer and Autoimmune Diseases
Mar 28th 2024, 09:00

When PD-1 receptors on T cells pair up, they are more likely to engage with PD-L1 proteins on other cells to prevent an immune attack. Credit: Donny Bliss/NIH

Your immune system should ideally recognize and attack infectious invaders and cancerous cells. But the system requires safety mechanisms, or brakes, to keep it from damaging healthy cells. To do this, T cells—the immune system’s most powerful attackers—rely on immune “checkpoints” to turn immune activation down when they receive the right signal. While these interactions have been well studied, a research team supported in part by NIH has made an unexpected discovery into how a key immune checkpoint works, with potentially important implications for therapies designed to boost or dampen immune activity to treat cancer and autoimmune diseases.1

The checkpoint in question is a protein called programmed cell death-1 (PD-1). Here’s how it works: PD-1 is a receptor on the surface of T cells, where it latches onto certain proteins, known as PD-L1 and PD-L2, on the surface of other cells in the body. When this interaction occurs, a signal is sent to the T cells that stops them from attacking these other cells.

Cancer cells often take advantage of this braking system, producing copious amounts of PD-L1 on their surface, allowing them to hide from T cells. An effective class of immunotherapy drugs used to treat many cancers works by blocking the interaction between PD-1 and PD-L1, to effectively release the brakes on the immune system to allow the T cells to unleash an assault on cancer cells. Researchers have also developed potential treatments for autoimmune diseases that take the opposite tact: stimulating PD-1 interaction to keep T cells inactive. These PD-1 “agonists” have shown promise in clinical trials as treatments for certain autoimmune diseases.

However, to fulfill the promise of these approaches for treating cancer and autoimmune diseases, a better understanding of precisely how PD-1 works to suppress T cell activity is still needed. The thinking has long been that individual PD-1 receptors act alone. But, as reported in (https://www.science.org/doi/10.1126/sciimmunol.ade6256) Science Immunology, it turns out that this may not usually be the case. A team led by (https://med.nyu.edu/faculty/jun-wang) Jun Wang and (https://med.nyu.edu/faculty/xiangpeng-kong) Xiangpeng Kong of New York University Langone Health’s Perlmutter Cancer Center, with Elliot Philips of NYU and Michael Dustin of the University of Oxford, U.K., used sophisticated techniques to look for evidence of what happens when PD-1 proteins work together in pairs.

They found that PD-1’s tendency to link, or not link, with a second PD-1 protein to form what’s known as a “dimer” depends on interactions with portions of the protein that cross the immune cell membrane. They also found that, when PD-1 receptors pair up, they do a better job of squashing immune responses. The findings also showed that a single change in the amino acid structure in the portion of PD-1 that crosses the cell membrane can strengthen or weaken immune responses.

One reason why these fundamental discoveries are exciting is they suggest that interfering with PD-1’s ability to form dimers might make immunotherapy treatments for cancer more effective. In addition, treatments that strengthen interactions between paired PD-1 receptors might aid in the design of promising new drug classes that are intended to tamp down inflammation seen in people with some autoimmune diseases, including rheumatoid arthritis, lupus, and type 1 diabetes. The research team now plans to conduct further investigations of PD-1 blockers and agonists to explore whether these findings could eventually lead to more effective treatments for both cancer and autoimmune diseases.

Reference:

[1] Philips EA, et al. (https://pubmed.ncbi.nlm.nih.gov/38457513/) Transmembrane domain-driven PD-1 dimers mediate T cell inhibition. Science Immunology. DOI: 10.1126/sciimmunol.ade6256 (2024).

NIH Support: National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences

(https://directorsblog.nih.gov/2024/03/26/welcoming-internet-pioneer-vint-cerf-for-rall-cultural-lecture-on-ai-in-biomedical-research/) Welcoming Internet Pioneer Vint Cerf for Rall Cultural Lecture on AI in Biomedical Research
Mar 26th 2024, 09:00

NIH Director Monica Bertagnolli in a fireside chat with Google Chief Internet Evangelist Vint Cerf at the Rall Cultural Lecture on March 19, 2024, at Masur Auditorium. Credit (all photos): Leslie Kossoff

Last week it was my pleasure to welcome to NIH Vinton “Vint” Cerf, a pioneer of the digital world widely known as one of the “fathers of the internet,” to speak at our annual (https://oir.nih.gov/wals/named-honorific-lectures/edward-rall-cultural-lecture) J. Edward Rall Cultural Lecture. We had a lively fireside chat focusing on “The Promises and Perils of AI in Biomedical Research and Health Care Delivery” that included discussions on topics like improving data collection, ensuring broad representativeness of the data being used to train AI and machine learning, expanding clinical research, and offering advice for scientists just starting out. It was an insightful, eye-opening conversation on a topic close to my heart. As NIH Director, I very much hope to deliver evidence-based health care to all people, and I’m excited about how AI and machine learning can help us advance toward that goal.

Dr. Cerf, who is vice president and Chief Internet Evangelist for Google, has too many awards to list, but just a few include the U.S. National Medal of Technology, the Turing Award, and the Presidential Medal of Freedom. He serves as an advisor to several government agencies, including the National Science Foundation, NASA, and the Departments of Defense, Energy, and Commerce.

The NIH Rall Cultural Lecture is held in honor of Dr. J. Edward Rall, who helped define the modern intramural research program at NIH. In the 1950s, he helped establish a stable, academic-minded, and culturally rich community within our rapidly expanding government agency. In 1984, he recommended that NIH add a cultural lecture to its Director’s Lecture series to enrich our scientific community.

As I said at the event, I’m grateful to Dr. Cerf for his visit and this conversation, and I can’t think of a more spectacular Rall Cultural Lecture than what he provided for all of us. You can watch the (https://videocast.nih.gov/watch=54305) full talk here.


(https://directorsblog.nih.gov/2024/03/14/study-suggests-during-sleep-neural-process-helps-clear-the-brain-of-damaging-waste/) Study Suggests During Sleep, Neural Process Helps Clear the Brain of Damaging Waste
Mar 14th 2024, 10:36

Artist’s rendering of neural activity clearing waste products through tight spaces of the brain. Credit: Donny Bliss/NIH

We’ve long known that sleep is a restorative process necessary for good health. Research has also shown that the accumulation of waste products in the brain is a leading cause of numerous neurological disorders, including (https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet) Alzheimer’s and (https://www.ninds.nih.gov/health-information/disorders/parkinsons-disease) Parkinson’s diseases. What hasn’t been clear is how the healthy brain “self-cleans,” or flushes out that detrimental waste.

But a new study by a research team supported in part by NIH suggests that a neural process that happens while we sleep helps cleanse the brain, leading us to wake up feeling rested and restored. Better understanding this process could one day lead to methods that help people function well on less sleep. It could also help researchers find potential ways to delay or prevent neurological diseases related to accumulated waste products in the brain.

The findings, reported in (https://pubmed.ncbi.nlm.nih.gov/38418877/) Nature, show that, during sleep, neural networks in the brain act like an array of miniature pumps, producing large and rhythmic waves through synchronous bursts of activity that propel fluids through brain tissue. Much like the process of washing dishes, where you use a rhythmic motion of varying speeds and intensity to clear off debris, this process that takes place during sleep clears accumulated metabolic waste products out.

The research team, led by (https://kipnislab.wustl.edu/) Jonathan Kipnis and Li-Feng Jiang-Xie at Washington University School of Medicine in St. Louis, wanted to better understand how the brain manages its waste. This is not an easy task, given that the human brain’s billions of neurons inevitably produce plenty of junk during cognitive processes that allow us to think, feel, move, and solve problems. Those waste products also build in a complex environment, including a packed maze of interconnected neurons, blood vessels, and interstitial spaces, surrounded by a protective blood-brain barrier that limits movement of substances in or out.

So, how does the brain move fluid through those tight spaces with the force required to get waste out? Earlier research suggested that neural activity during sleep might play an important role in those waste-clearing dynamics. But previous studies hadn’t pinned down the way this works.

To learn more in the new study, the researchers recorded brain activity in mice. They also used an ultrathin silicon probe to measure fluid dynamics in the brain’s interstitial spaces. In awake mice, they saw irregular neural activity and only minor fluctuations in the interstitial spaces. But when the animals were resting under anesthesia, the researchers saw a big change. Brain recordings showed strongly enhanced neural activity, with two distinct but tightly coupled rhythms. The research team realized that the structured wave patterns could generate strong energy that could move small molecules and peptides, or waste products, through the tight spaces within brain tissue.

To make sure that the fluid dynamics were really driven by neurons, the researchers used tools that allowed them to turn neural activity off in some areas. Those experiments showed that, when neurons stopped firing, the waves also stopped. They went on to show similar dynamics during natural sleep in the animals and confirmed that disrupting these neuron-driven fluid dynamics impaired the brain’s ability to clear out waste.

These findings highlight the importance of this cleansing process during sleep for brain health. The researchers now want to better understand how specific patterns and variations in those brain waves lead to changes in fluid movement and waste clearance. This could help researchers eventually find ways to speed up the removal of damaging waste, potentially preventing or delaying certain neurological diseases and allowing people to need less sleep.

Reference:

[1] Jiang-Xie LF, et al. (https://pubmed.ncbi.nlm.nih.gov/38418877/) Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature. DOI: 10.1038/s41586-024-07108-6 (2024).

NIH Support: National Center for Complementary and Integrative Health

(https://directorsblog.nih.gov/2024/03/07/healing-switch-links-acute-kidney-injury-to-fibrosis-suggesting-way-to-protect-kidney-function/) Healing Switch Links Acute Kidney Injury to Fibrosis, Suggesting Way to Protect Kidney Function
Mar 7th 2024, 09:00

The protein Sox9 switches on after kidney injury, then back off after repair. When healing doesn’t proceed optimally, Sox9 stays on, leading to scarring and fibrosis. Credit: Donny Bliss/NIH

Healthy (https://www.niddk.nih.gov/health-information/kidney-disease/kidneys-how-they-work) kidneys—part of the urinary tract—remove waste and help balance chemicals and fluids in the body. However, our kidneys have a limited ability to regenerate healthy tissue after sustaining injuries from conditions such as diabetes or high blood pressure. Injured kidneys are often left with a mix of healthy and scarred tissue, or fibrosis, which over time can compromise their function and lead to chronic kidney disease or complete kidney failure. (https://www.cdc.gov/kidneydisease/publications-resources/ckd-national-facts.html) More than one in seven adults in the U.S. are estimated to have chronic kidney disease, according to the Centers for Disease Control and Prevention, most without knowing it.

Now, a team of researchers led by (https://researchers.cedars-sinai.edu/Sanjeev.Kumar) Sanjeev Kumar at Cedars-Sinai Medical Center, Los Angeles, has identified a key molecular “switch” that determines whether injured kidney tissue will heal or develop those damaging scars.1 Their findings, reported in the journal (https://pubmed.ncbi.nlm.nih.gov/38386758/) Science, could lead to new and less invasive ways to detect fibrosis in the kidneys. The research could also point toward a targeted therapeutic approach that might prevent or reverse scarring to protect kidney function.

In earlier studies, the research team found that a protein called Sox9 plays an important role in switching on the repair response in kidneys after acute injury.2 In some cases, the researchers noticed that Sox9 remained active for a prolonged period of a month or more. They suspected this might be a sign of unresolved injury and repair.

By conducting studies using animal models of kidney damage, the researchers found that cells that turned Sox9 on and then back off healed without fibrosis. However, cells that failed to regenerate healthy kidney cells kept Sox9 on indefinitely, which in turn led to the production of fibrosis and scarring.

According to Kumar, Sox9 appears to act like a sensor, switching on after injury. Once restored to health, Sox9 switches back off. When healing doesn’t proceed optimally, Sox9 stays on, leading to scarring. Importantly, the researchers also found they could encourage kidneys to recover by forcing Sox9 to turn off a week after an injury, suggesting it may be a promising drug target.

The researchers also looked for evidence of this process in human patients who have received kidney transplants. They could see that, when transplanted kidneys took longer to start working, Sox9 was switched on. Those whose kidneys continued to produce Sox9 also had lower kidney function and more scarring compared to those who didn’t. 

The findings suggest that the dynamics observed in animal studies may be clinically relevant in people, and that treatments targeting Sox9 might promote kidneys to heal instead of scarring. The researchers say they hope that similar studies in the future will lead to greater understanding of healing and fibrosis in other organs—including the heart, lungs, and liver—with potentially important clinical implications.

References:

[1] Aggarwal S, et al. (https://pubmed.ncbi.nlm.nih.gov/38386758/) SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys. Science. DOI: 10.1126/science.add6371 (2024).

[2] Kumar S, et al. (https://pubmed.ncbi.nlm.nih.gov/26279573/) Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney. Cell Reports. DOI: 10.1016/j.celrep.2015.07.034 (2015).

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases

(https://directorsblog.nih.gov/2024/02/29/aided-by-ai-study-uncovers-hidden-sex-differences-in-dynamic-brain-function/) Aided by AI, Study Uncovers Hidden Sex Differences in Dynamic Brain Function
Feb 29th 2024, 10:40

Credit: Adobe/Feodora

We’re living in an especially promising time for biomedical discovery and advances in the delivery of data-driven health care for everyone. A key part of this is the tremendous progress made in applying artificial intelligence to study human health and ultimately improve clinical care in many important and sometimes surprising ways.1 One new example of this comes from a fascinating study, supported in part by NIH, that uses AI approaches to reveal meaningful sex differences in the way the brain works.

As reported in the (https://pubmed.ncbi.nlm.nih.gov/38377194/) Proceedings of the National Academy of Sciences, researchers led by (https://med.stanford.edu/profiles/vinod-menon) Vinod Menon at Stanford Medicine, Stanford, CA, have built an AI model that can—nine times out of ten—tell whether the brain in question belongs to a female or male based on scans of brain activity alone.2 These findings not only help resolve long-term debates about whether reliable differences between sexes exist in the human brain, but they’re also a step toward improving our understanding of why some psychiatric and neurological disorders affect women and men differently.

The prevalence of certain psychiatric and neurological disorders in men and women can vary significantly, leading researchers to suspect that sex differences in brain function likely exist. For example, studies have found that females are more likely to experience depression, anxiety, and eating disorders, while autism, Attention-Deficit/Hyperactivity Disorder, and schizophrenia are seen more often in males. But earlier research to understand sex differences in the brain have focused mainly on anatomical and structural studies of brain regions and their connections. Much less is known about how those structural differences translate into differences in brain activity and function.

To help fill those gaps in the new study, Menon’s team took advantage of vast quantities of brain activity data from MRI scans from the NIH-supported (https://www.humanconnectome.org/) Human Connectome Project. The data was captured from hundreds of healthy young adults with the goal of studying the brain and how it changes with growth, aging, and disease. To use this data to explore sex differences in brain function, the researchers developed what’s known as a deep neural network model in which a computer “learned” how to recognize patterns in brain activity data that could distinguish a male from a female brain.

This approach doesn’t rely on any preconceived notions about what features might be important. A computer is simply shown many examples of brain activity belonging to males and females and, over time, can begin to pick up on otherwise hidden differences that are useful for making such classifications accurately. One of the things that made this work different from earlier attempts was it relied on dynamic scans of brain activity, which capture the interplay among brain regions.

After analyzing about 1,500 brain scans, a computer could usually (although not always) tell whether a scan came from a male or female brain. The findings also showed the model worked reliably well in different datasets and in brain scans for people in different places in the U.S. and Europe. Overall, the findings confirm that reliable sex differences in brain activity do exist.

Where did the model find those differences? To get an idea, the researchers turned to an approach called explainable AI, which allowed them to dig deeper into the specific features and brain areas their model was using to pick up on sex differences. It turned out that one set of areas the model was relying on to distinguish between male and female brains is what’s known as the default mode network. This area is responsible for processing self-referential information and constructing a coherent sense of the self and activates especially when people let their minds wander.3 Other important areas included the striatum and limbic network, which are involved in learning and how we respond to rewards, respectively.

Many questions remain, including whether such differences arise primarily due to inherent biological differences between the sexes or what role societal circumstances play. But the researchers say that the discovery already shows that sex differences in brain organization and function may play important and overlooked roles in mental health and neuropsychiatric disorders. Their AI model can now also be applied to begin to explain other kinds of brain differences, including those that may affect learning or social behavior. It’s an exciting example of AI-driven progress and good news for understanding variations in human brain functions and their implications for our health.

References:

[1] Bertagnolli, MM. (https://academic.oup.com/pnasnexus/article/2/12/pgad356/7477226?login=false) Advancing health through artificial intelligence/machine learning: The critical importance of multidisciplinary collaboration. PNAS Nexus. DOI: 10.1093/pnasnexus/pgad356 (2023).

[2] Ryali S, et al. (https://pubmed.ncbi.nlm.nih.gov/38377194/) Deep learning models reveal replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization. Proc Natl Acad Sci. DOI: 10.1073/pnas.2310012121 (2024).

[3] Menon, V. (https://www.sciencedirect.com/science/article/pii/S0896627323003082?via%3Dihub) 20 years of the default mode network: A review and synthesis. Neuron.DOI: 10.1016/j.neuron.2023.04.023 (2023).

NIH Support: National Institute of Mental Health, National Institute of Biomedical Imaging and Bioengineering, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging

(https://directorsblog.nih.gov/2024/02/27/celebrating-new-clinical-center-exhibit-for-nobel-laureate-dr-harvey-alter/) Celebrating New Clinical Center Exhibit for Nobel Laureate Dr. Harvey Alter
Feb 27th 2024, 15:00

On Feb. 14, 2024, NIH hosted an event to open an exhibit on display in the NIH Clinical Center in Bethesda, Maryland, titled, “Harvey Alter and the Discovery of Hepatitis C: Making Our Blood Supply Safe.” Left to right: Anthony Fauci, distinguished professor at the Georgetown University School of Medicine and the McCourt School of Public Policy; Diane Dowling (Harvey Alter’s wife); honoree Harvey Alter; James Gilman, Chief Executive Officer of the NIH Clinical Center; NIH Director Monica Bertagnolli; and NIH Principal Deputy Director Lawrence Tabak. Credit: Chia-Chi Charlie Chang, NIH

Earlier this month, I had the great honor of attending the opening of an exhibit at the NIH Clinical Center commemorating the distinguished career of (https://irp.nih.gov/pi/harvey-alter) Dr. Harvey Alter. Harvey’s collaborators, colleagues, and family members joined him to celebrate this display dedicated to his groundbreaking hepatitis C work developed by the (https://history.nih.gov/) Office of NIH History and Stetten Museum.

As I remarked at the event, we at NIH are proud to be able to claim Harvey as our own. He has spent almost the entirety of his professional career at the Clinical Center, working as a scientist in the Department of Transfusion Medicine since the 1960s.

Those who view this permanent exhibit will learn about how Harvey’s dedicated research has transformed the safety of the U.S. blood supply. Before the 1970s, nearly a third of patients who received multiple, lifesaving blood transfusions contracted hepatitis. Today, the risk of contracting hepatitis from a blood transfusion is essentially zero, thanks largely to Harvey’s research advances, including his work to identify the hepatitis C virus, which earned him the 2020 Nobel Prize in Physiology or Medicine. A cure for hepatitis C became available in 2014, and former NIH Director Dr. Francis Collins, who was at the event, has been working with President Biden to ensure greater access to these medications as part of an effort to eliminate hepatitis C in this country. This important work would not have been possible without Harvey’s foundational discoveries. Harvey is one of six Nobelists who did the entirety of their award-winning research at NIH as federal scientists, and the only NIH Nobel laureate to be recognized for clinical research.

This exhibit in the busy halls of the Clinical Center is a good reminder to the many who pass by of why we do what we do: It can take long hours and many years, but we can make a significant impact in clinical care when we try to understand the root causes of problems. Please stop by when you’re there to learn more about Harvey’s remarkable career.


(https://directorsblog.nih.gov/2024/02/22/a-potential-new-way-to-prevent-noise-induced-hearing-loss-trapping-excess-zinc/) A Potential New Way to Prevent Noise-Induced Hearing Loss: Trapping Excess Zinc
Feb 22nd 2024, 10:00

Zinc in the inner ear is concentrated in stereocilia essential for hearing, but a new study finds that loud sounds cause damaging dysregulation of the essential mineral that can lead to noise-induced hearing loss. Credit: Donny Bliss/NIH

Hearing loss is a pervasive problem, affecting one in eight people aged 12 and up in the U.S.1 While hearing loss has multiple causes, an important one for millions of people is exposure to loud noises, which can lead to gradual hearing loss, or people can lose their hearing all at once. The only methods used to prevent (https://www.nidcd.nih.gov/health/noise-induced-hearing-loss) noise-induced hearing loss today are avoiding loud noises altogether or wearing earplugs or other protective devices during loud activities. But findings from an intriguing new NIH-supported (https://www.pnas.org/doi/10.1073/pnas.2310561121) study exploring the underlying causes of this form of hearing loss suggest it may be possible to protect hearing in a different way: with treatments targeting excess and damaging levels of zinc in the inner ear.

The new findings, reported in the Proceedings of the National Academy of Sciences, come from a team led by (http://phrc.pitt.edu/people/thanos-tzounopoulos) Thanos Tzounopoulos, (https://www.cnup.pitt.edu/people/amantha-thathiah-phd) Amantha Thathiah, and (https://www.cnup.pitt.edu/people/christopher-cunningham-phd) Chris Cunningham, at the University of Pittsburgh.2 The research team is focused on understanding how hearing works, as well as developing ways to treat hearing loss and (https://www.nidcd.nih.gov/health/tinnitus) tinnitus (the perception of sound, like ringing or buzzing, that doesn’t have an external source), which both can arise from loud noises.

Previous studies have shown that traumatic noises of varying durations and intensities can lead to different types of damage to cells in the cochlea, the fluid-filled cavity in the inner ear that plays an essential role in hearing. For instance, in mouse studies, noise equivalent to a blasting rock concert caused the loss of tiny sound-detecting hair cells and essential supporting cells in the cochlea, leading to hearing loss. Milder noises comparable to the sound of a hand drill can lead to subtler hearing loss, as essential connections, or synapses, between hair cells and sensory neurons are lost.

To better understand why this happens, the research team wanted to investigate the underlying cellular- and molecular-level events and signals responsible for inner ear damage and irreversible hearing loss caused by loud sounds. They looked to (https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/) zinc, an essential mineral in our diets that plays many important roles in the body. Interestingly, zinc concentrations in the inner ear are highest of any organ or tissue in the body. But, despite this, the role of zinc in the cochlea and its effects on hearing and hearing loss hadn’t been studied in detail.

Most zinc in the body—about 90%—is bound to proteins. But the researchers were interested in the approximately 10% of zinc that’s free-floating, due to its important role in signaling in the brain and other parts of the nervous system. They wanted to find out what happens to the high concentrations of zinc in the mouse cochlea after traumatic levels of noise, and whether targeting zinc might influence inner ear damage associated with hearing loss.

The researchers found that, hours after mice were exposed to loud noise, zinc levels in the inner ear spiked and were dysregulated in the hair cells and in key parts of the cochlea, with significant changes to their location inside cells. Those changes in zinc were associated with cellular damage and disrupted communication between sensory cells in the inner ear.

The good news is that this discovery suggested a possible solution: inner ear damage and hearing loss might be averted by targeting excess zinc. And their subsequent findings suggest that it works. Studies in mice that were treated with a slow-releasing compound in the inner ear were protected from noise-induced damage and associated hearing loss. The treatment involves a chemical compound known as a zinc chelating agent, which binds and traps excess free zinc, thus limiting cochlear damage and hearing loss.

Will this strategy work in people? We don’t know yet. However, the researchers report that they’re planning to pursue preclinical safety studies of the new treatment approach. Their hope is to one day make a zinc-targeted treatment readily available to protect against noise-induced hearing loss. But, for now, the best way to protect your hearing while working with noisy power tools or attending a rock concert is to remember your ear protection.

References:

[1] (https://www.nidcd.nih.gov/health/statistics/quick-statistics-hearing) Quick Statistics About Hearing. National Institute on Deafness and Other Communication Disorders.

[2] Bizup B, et al. (https://doi.org/10.1073/pnas.2310561121) Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery. PNAS. DOI: (https://doi.org/10.1073/pnas.2310561121) 10.1073/pnas.2310561121 (2024).

NIH Support: National Institute on Deafness and Other Communication Disorders, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering

(https://directorsblog.nih.gov/2024/02/15/study-offers-new-clues-to-why-most-people-with-autoimmune-diseases-are-women/) Study Offers New Clues to Why Most People with Autoimmune Diseases Are Women
Feb 15th 2024, 09:07

Xist molecules shut down one of two female X chromosomes to avoid toxic protein levels, but they may also play a role in triggering autoimmune diseases. Credit: Donny Bliss/NIH

As many as 50 million Americans have one of more than 100 known (https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases#:~:text=More%20than%2080%20diseases%20occur,erythematosus%2C%20and%20inflammatory%20bowel%20disease.) autoimmune diseases, making it the third most prevalent disease category, surpassed only by cancer and heart disease.1,2 This category of disease has also long held a mystery: Why are most people with a chronic autoimmune condition—as many as four out of every five—women? This sex-biased trend includes autoimmune diseases such as (https://www.niams.nih.gov/health-topics/rheumatoid-arthritis) rheumatoid arthritis, (https://www.ninds.nih.gov/health-information/disorders/multiple-sclerosis) multiple sclerosis, (https://www.niams.nih.gov/health-topics/scleroderma) scleroderma, (https://www.niams.nih.gov/health-topics/lupus) lupus, (https://www.niams.nih.gov/health-topics/sjogrens-syndrome) Sjögren’s syndrome, and many others.

Now, exciting findings from a (https://www.cell.com/cell/fulltext/S0092-8674(24)00002-3) study supported in part by NIH provide a clue to why this may be the case, with potentially important implications for the early detection, treatment, and prevention of autoimmune diseases. The new evidence, reported in the journal Cell, suggests that more women develop autoimmune diseases than men due in part to the most fundamental difference between the biological sexes: that females have two X chromosomes, while males have an X and a Y. More specifically, it has to do with molecules called Xist (pronounced “exist”), which are encoded on the X chromosome and transcribed into long non-coding stretches of RNA, only when there are two X chromosomes.

Those long Xist molecules wind themselves around sections of just one of a female’s two X chromosomes, shutting down the extra X chromosome in a process known as X-chromosome inactivation. It’s an essential process to ensure those cells won’t produce too many proteins encoded on X chromosomes, which would be a deadly mistake. It’s also something that males, with a single X chromosome and much smaller Y chromosome carrying almost no working genes, don’t have to worry about.

The new findings come from a team at Stanford University School of Medicine, Stanford, CA, led by (https://u12097671.ct.sendgrid.net/ls/click?upn=9rudYHeevExQpJ5A1h-2BA7S6bW9XxPN4Z7BQChTk7hLHdyZ4EJl8MYnjud1wd-2Fx-2FNmLLZ33EzMZSiSlruMGN6DQ-3D-3DCYxR_tCOQBiHShQdVG5GRtINbKo-2BsiS8Vm-2FLCH1GX-2BhwH2usnJyuyruNW0r-2F7jCoGUMU-2BJUvqzWbeVELMxdhhoy-2FIKGL5mXBUZu4a2yiFQ1WcL5PeOc1mSiY7Z4-2FgXJMfL185XoW49I8m92uhVrj0VAchHa7sKwHQWRqJaw-2FdE0wVLxj-2BGmV9O7NZhnE-2BHQnfz7HeDHbpR9JPqulSynkWYe8sUXITkMqHuN-2FLoGSafSjdET3VK64a38k-2By-2FyhLm2z4sOz1QpT58BGcD4jINfx6xN-2FuPHZMU2vC1eUsW1GV2VxxFy0Scxz-2BsTk-2FXkg6w6G3Gk7iSgjXu2J8LCu-2BXqvjrWls7PvKe4K1xWjbuQIj59-2F46grtlw66flUPiOobKXl3jh-2FmCqYsMsxGnCR0l6LZd6GjmDa4NDalVynqy0WvkQCedw5zYBsZOV5OlQsA5iVxu2-2B5wn8yQigZBYss0buieElXUo2gU-2FsESlWWwtUY3QYKZ-2BBvPQipaxuHx-2BDLtNX9O9hDDWMal87U8-2FBlefva7UvQmO8msazftw3dATA6puiCReaLxAObEk7QteDiMlRKl6K4Kmbm0Gcjx2EWsprU2azYFqOT3QlFgOvdgP1y3fFziw-3D) Howard Chang and (https://profiles.stanford.edu/diana-dou) Diana Dou. What they suggest is that while Xist molecules play an essential role in X-chromosome inactivation, they also have a more nefarious ability to encourage the formation of odd clumps of RNA, DNA, and proteins that can in turn trigger strong autoimmune responses.

In earlier research, the team identified about 80 different proteins that bind to Xist either directly or indirectly. After taking a close look at the list, the researchers realized that many of the proteins had been shown to play some role in autoimmune conditions. This raised an intriguing question: Could the reason women develop autoimmune diseases so much more often than men be explained by those Xist-containing clumps?

To test the idea, the researchers first decided to study it in male mice. They made two different strains of male mice produce Xist to see if it would increase their risk for autoimmunity in ways they could measure. And it did. The researchers found that once Xist was activated in male mice that were genetically prone to autoimmunity, they became more susceptible to developing a lupus-like condition. It didn’t happen in every individual, which suggests, not surprisingly, that the development of autoimmune disease requires additional triggers as well.

In addition, in a different mouse strain that was resistant to developing autoimmunity, the addition of Xist in males wasn’t enough to cause autoimmunity, the researchers found. That also makes sense in that, while women are much more prone to developing autoimmune disease, most people don’t. Xist complexes likely lead to autoimmunity only when certain genetic and other factors are met.

The researchers also examined blood samples from 100 people with autoimmune conditions and found they had antibodies to many of their own Xist complexes. Some of those antibodies also appeared specific to a certain autoimmune disorder, suggesting that they might be useful for tests that could detect autoimmunity or particular autoimmune conditions even before symptoms arise.

There are still many questions to explore in future research, including why men sometimes do get autoimmune conditions, and what other key triggers drive the development of autoimmunity. But this fundamentally important discovery points to potentially new ways to think about the causes for the autoimmune conditions that affect so many people in communities here and around the world.

References:

[1] The American Autoimmune Related Diseases Association. (https://autoimmune.org/wp-content/uploads/2019/12/1-in-5-Brochure.pdf) Autoimmune Facts.

[2] Dou DR, et al. (https://pubmed.ncbi.nlm.nih.gov/38306984/) Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. DOI: 10.1016/j.cell.2023.12.037. (2024).

NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases

(https://directorsblog.nih.gov/2024/02/13/understanding-childbirth-through-a-single-cell-atlas-of-the-placenta/) Understanding Childbirth Through a Single-Cell Atlas of the Placenta
Feb 13th 2024, 09:02

A person in labor. Credit: Adobe/Prostock-studio

While every birth story is unique, many parents would agree that going into labor is an unpredictable process. Although most pregnancies last about 40 weeks, about one in every 10 infants in the U.S. are born before the 37th week of pregnancy, when their brain, lungs, and liver are still developing.1 Some pregnancies also end in an unplanned emergency caesarean delivery after labor fails to progress, for reasons that are largely unknown. Gaining a better understanding of what happens during healthy labor at term may help to elucidate why labor doesn’t proceed normally in some cases.

In a recent development, NIH scientists and their colleagues reported some fascinating new findings that could one day give healthcare providers the tools to better understand and perhaps even predict labor.2 The research team produced an atlas showing the patterns of gene activity that take place in various cell types during labor. To create the atlas, they examined tissues from the placentas of 18 patients not in labor who underwent caesarean delivery and 24 patients in labor. The researchers also analyzed blood samples from another cohort of more than 250 people who delivered at various timepoints. This remarkable study, published in Science Translational Medicine, is the first to analyze gene activity at the single-cell level to better understand the communication that occurs between maternal and fetal cells and tissues during labor.

The placenta is an essential organ for bringing nutrients and oxygen to a growing fetus. It also removes waste, provides immune protection, and supports fetal development. The placenta participates in the process of normal labor at term and preterm labor. Problems with the placenta can lead to many issues, including preterm birth. To create the placental atlas, the study team used an approach called (https://commonfund.nih.gov/singlecell) single-cell RNA sequencing. Messenger RNA molecules transcribed or copied from DNA serve as templates for proteins, including those that send important signals between tissues. By sequencing RNAs at the single-cell level, it’s possible to examine gene activity and signaling patterns in many thousands of individual cells at once. This method allows scientists to capture and describe in detail the activities within individual cell types along with interactions among cells of different types and in immune or other key signaling pathways.

Using this approach, the researchers found that cells in the chorioamniotic membranes, which surround the fetus and rupture as part of the labor and delivery process, showed the greatest changes. They also found cells in the mother and fetus that were especially active in generating inflammatory signals. They note that these findings are consistent with previous research showing that inflammation plays an important role in sustaining labor.

Gene activity patterns and changes in the placenta can only be studied after the placenta is delivered. However, it would be ideal if these changes could be identified in the bloodstream of mothers earlier in pregnancy—before labor—so that health care providers can intervene if necessary. The recent study showed that this was possible: Certain gene activity patterns observed in placental cells during labor could be detected in blood tests of women earlier in pregnancy who would later go on to have a preterm birth. The authors note that more research is needed to validate these findings before they can be used as a clinical tool.  

Overall, these findings offer important insight into the underlying biology that normally facilitates healthy labor and delivery. They also offer preliminary proof-of-concept evidence that placental biomarkers present in the bloodstream during pregnancy may help to identify pregnancies at increased risk for preterm birth. While much more work and larger studies are needed, these findings suggest that it may one day be possible to identify those at risk for a difficult or untimely labor, when there is still opportunity to intervene.

The research was conducted by the Pregnancy Research Branch part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and led by Roberto Romero, M.D., D.Med.Sci., NICHD; Nardhy Gomez-Lopez, Ph.D., Washington University School of Medicine in St. Louis; and Roger Pique-Regi, Ph.D., Wayne State University, Detroit.

References:

[1] (https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm#:~:text=In%202022%2C%20preterm%20birth%20affected,in%20preterm%20birth%20rates%20remain.) Preterm Birth. CDC.

[2] Garcia-Flores V, et al., (https://www.science.org/doi/10.1126/scitranslmed.adh8335) Deciphering maternal-fetal crosstalk in the human placenta during parturition using single-cell RNA sequencing. Science Translational Medicine DOI: 10.1126/scitranslmed.adh8335 (2024).

NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development

(https://directorsblog.nih.gov/2024/02/08/whats-behind-that-morning-migraine-community-based-study-points-to-differences-in-perceived-sleep-quality-energy-on-the-previous-day/) What’s Behind that Morning Migraine? Community-Based Study Points to Differences in Perceived Sleep Quality, Energy on the Previous Day
Feb 8th 2024, 10:30

Credit: Adobe Stock/nenetus

(https://www.ninds.nih.gov/health-information/disorders/headache) Headaches are the most common form of pain and a major reason people miss work or school. Recurrent attacks of (https://www.ninds.nih.gov/health-information/disorders/migraine) migraine headaches can be especially debilitating, involving moderate to severe throbbing and pulsating pain on one side of the head that sometimes lasts for days. Migraines and severe headaches affect about 1 in 5 women and about 1 in 10 men, making them one of the most prevalent of all neurological disorders.1 And yet there’s still a lot we don’t know about what causes headaches or how to predict when one is about to strike.

Now a new (https://pubmed.ncbi.nlm.nih.gov/38266217/#:~:text=Whereas%20poorer%20sleep%20quality%20and,onsets%20later%20in%20the%20day.) NIH-led study reported in the journal Neurology has some important insight.2 One of the things I especially appreciate about this new work is that it was conducted in a community setting rather than through a specialty clinic, with people tracking their own headache symptoms, sleep, mood, and more on a mobile phone app while they went about their daily lives. It means that the findings are extremely relevant to the average migraine sufferer who shows up in a primary care doctor’s office looking for help for their recurrent headaches.

The study, led by (https://www.nimh.nih.gov/research/research-conducted-at-nimh/principal-investigators/kathleen-merikangas) Kathleen Merikangas at NIH’s National Institute of Mental Health, Bethesda, MD, is part of a larger, community-based (https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/geb-sdge/current-studies) Family Study of Affective and Anxiety Spectrum Disorders. This ongoing study enrolls volunteers from the greater Washington, D.C., area with a range of disorders, including bipolar disorders, major depression, anxiety disorders, sleep disorders, and migraine along with their immediate family members. It also includes people with none of these disorders who serve as a control group. The goal is to learn more about the frequency of mood and other mental and physical disorders in families and how often they co-occur. This information can provide insight into the nature and causes for all these conditions.

While there will be much more to come from this ambitious work, the primary aim for this latest study was to look for links between a person’s perceived mood, sleep, energy, and stress and their likelihood for developing a headache. The study’s 477 participants, aged 7 to 84, included people with and without migraines who were also assessed for mood, anxiety, sleep disorders and other physical conditions. Women accounted for 291 of the study’s participants. Each were asked to track their emotional states, including anxiousness, mood, energy, stress, and headaches four times each day for two weeks. Each morning, they also reported on their sleep the night before.

The data showed that people with a morning migraine reported poorer quality sleep the night before. They also reported lower energy the day before. Interestingly, those factors didn’t lead to an increased risk of headaches in the afternoon or evening. Afternoon or evening headaches were more often preceded by higher stress levels or having higher-than-average energy the day before.

More specifically, people with poorer perceived sleep quality on average had a 22 percent greater chance for a headache attack the next morning. A decrease in the self-reported usual quality of sleep was also associated with an 18 percent increased chance of a headache the next morning. Similarly, a drop in the usual level of energy on the prior day was associated with a 16 percent greater chance of headache the next morning. In contrast, greater average levels of stress and substantially higher energy than usual the day before was associated with a 17 percent increased chance of headache later the next day.

Surprisingly, the study didn’t find any connection between feeling anxious or depressed with headaches on the next day after considering energy and sleep. However, Merikangas emphasizes that participants’ perceived differences in energy and sleep may not reflect objective measures of sleep patterns or energy, suggesting that the connection may still be based on changes in a person’s feelings about their underlying physical or emotional state in complex ways.

The findings suggest that changes in the body and brain are already taking place before a person first feels a headache, suggesting it may be possible to predict and prevent migraines or other headaches. It also adds to evidence for the usefulness of diaries or apps for headache sufferers to track their sleep, health, behavioral, and emotional states in real time to better understand and manage headache pain. Meanwhile, the researchers report that they’re continuing to explore other factors that may precede and trigger headaches, including dietary factors, changes in a person’s physiology such as stress hormone levels, and environmental factors, including weather, seasonal changes, and geography.

References:

[1] American Headache Society. (https://americanheadachesociety.org/news/journal-prevalence-migraine-severe-headache/) The Prevalence of Migraine and Severe Headache.

[2] Lateef TM, et al. (https://pubmed.ncbi.nlm.nih.gov/38266217/#:~:text=Whereas%20poorer%20sleep%20quality%20and,onsets%20later%20in%20the%20day.) Association Between Electronic Diary-Rated Sleep, Mood, Energy, and Stress With Incident Headache in a Community-Based Sample. Neurology. DOI: 10.1212/WNL.0000000000208102. (2024).

NIH Support: National Institute of Mental Health

(https://directorsblog.nih.gov/2024/02/01/findings-in-tuberculosis-immunity-point-toward-new-approaches-to-treatment-and-prevention/) Findings in Tuberculosis Immunity Point Toward New Approaches to Treatment and Prevention
Feb 1st 2024, 16:30

Researchers gave one group of mice a contained infection with the bacteria that causes TB and immunized another. Later when exposed to TB, macrophages from each group turned on two separate inflammation programs. Credit: Donny Bliss/NIH

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis (Mtb), took 1.3 million lives in 2022, making it the (https://www.who.int/news-room/fact-sheets/detail/tuberculosis) second leading infectious killer around the world after COVID-19, according to the World Health Organization. Current TB treatments require months of daily medicine, and certain cases of TB are becoming increasingly difficult to treat because of drug resistance. While TB case counts had been steadily decreasing before the COVID-19 pandemic, there’s been an uptick in the last couple of years.

Although a TB vaccine exists and offers some protection to young children, the vaccine, known as (https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm) BCG, has not effectively prevented TB in adults. Developing more protective and longer lasting TB vaccines remains an urgent priority for NIH. As part of this effort, NIH’s Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers ((https://www.niaid.nih.gov/research/immune-mechanisms-protection-mycobacterium-tuberculosis) IMPAc(https://www.niaid.nih.gov/research/immune-mechanisms-protection-mycobacterium-tuberculosis) -TB) are working to learn more about how we can harness our immune systems to mount the best protection against Mtb. And I’m happy to share some encouraging results now reported in the journal PLoS Pathogens, which show progress in understanding TB immunity and suggest additional strategies to fight this deadly bacterial infection in the future.1

Most vaccines work by stimulating our immune systems to produce antibodies that target a specific pathogen. The antibodies work to protect us from getting sick if we are ever exposed to that pathogen in the future. However, the body’s more immediate but less specific response against infection, called the innate immune system, serves as the first line of defense. The innate immune system includes cells known as macrophages that gobble up and destroy pathogens while helping to launch inflammatory responses that help you fight an infection.

In the case of TB, here’s how it works: If you were to inhale Mtb bacteria into your lungs, macrophages in tiny air sacs called alveoli would be the first to encounter it. When these alveolar macrophages meet Mtb for the first time, they don’t mount a strong attack against them. In fact, Mtb can infect these immune macrophages to produce more bacteria for a week or more.

What this intriguing new study led by (https://www.umass.edu/veterinary-animal-sciences/research-faculty/alissa-c-rothchild) Alissa Rothchild at the University of Massachusetts Amherst and colleagues from Seattle Children’s Research Institute suggests is that vaccines could target this innate immune response to change the way macrophages in the lungs respond and bolster overall defenses. How would it work? While scientists are just beginning to understand it, it turns out that the adaptive immune system isn’t the only part of our immune system that’s capable of adapting. The innate immune system also can undergo long-term changes, or remodeling, based on its experiences. In the new study, the researchers wanted to explore the various ways alveolar macrophages could respond to Mtb.

In search of ways to do it, the study’s first author, Dat Mai at Seattle Children’s Research Institute, conducted studies in mice. The first group of mice received the BCG vaccine. In the second model, the researchers put Mtb into the ears of mice to cause a persistent but contained infection in their lymph nodes. They’d earlier shown that this contained Mtb infection affords animals some protection against subsequent Mtb infections. A third group of mice—the control group—did not receive any intervention. Weeks later, all three groups of mice were exposed to aerosol Mtb infection under controlled conditions. The researchers then sorted infected macrophages from their lungs for further study.

Alveolar macrophages from the first two sets of mice showed a strong inflammatory response to subsequent Mtb exposure. However, those responses differed: The macrophages from vaccinated mice turned on one type of inflammatory program, while macrophages from mice exposed to the bacteria itself turned on another type. Further study showed that the different exposure scenarios led to other discernable differences in the macrophages that now warrant further study.

The findings show that macrophages can respond significantly differently to the same exposure based on what has happened in the past. They complement earlier findings that BCG vaccination can also lead to long-term effects on other subsets of innate immune cells, including myeloid cells from bone marrow.2,3 The researchers suggest there may be ways to take advantage of such changes to devise new strategies for preventing or treating TB by strengthening not just the adaptive immune response but the innate immune response as well.

As part of the IMPAc-TB Center led by (https://www.seattlechildrens.org/research/centers-programs/global-infectious-disease-research/research-areas-and-labs/urdahl-lab/) Kevin Urdahl at Seattle Children’s Research Institute, the researchers are now working with Gerhard Walzl and Nelita du Plessis at Stellenbosch University in South Africa to compare the responses in mice to those in human alveolar macrophages collected from individuals across the spectrum of TB disease. As they and others continue to learn more about TB immunity, the hope is to apply these insights toward the development of new vaccines that could combat this disease more effectively and ultimately save lives.

References:

[1] Mai D, et al. (https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011871) Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection. PLoS Pathogens. DOI: 10.1371/journal.ppat.1011871. (2024).

[2] Kaufmann E, et al. (https://doi.org/10.1016/j.cell.2017.12.031) BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. DOI: 10.1016/j.cell.2017.12.031 (2018).

[3] Lange C, et al. (https://pubmed.ncbi.nlm.nih.gov/34506734/) 100 years of Mycobacterium bovis bacille Calmette-Guérin. Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(21)00403-5. (2022).

 NIH Support: National Institute of Allergy and Infectious Diseases

(https://directorsblog.nih.gov/2024/01/18/new-findings-in-football-players-may-aid-the-future-diagnosis-and-study-of-chronic-traumatic-encephalopathy-cte/) New Findings in Football Players May Aid the Future Diagnosis and Study of Chronic Traumatic Encephalopathy (CTE)
Jan 18th 2024, 10:45

A new study found injuries to the white matter in football players who had experienced repetitive head impacts. Credit: Adobe Stock/Guido Amrein/merydolla

Repeated hits to the head—whether from boxing, playing American football or experiencing other repetitive head injuries—can increase someone’s risk of developing a serious neurodegenerative condition called (https://www.ninds.nih.gov/current-research/focus-disorders/focus-traumatic-brain-injury-research) chronic traumatic encephalopathy (CTE). Unfortunately, CTE can only be diagnosed definitively after death during an autopsy of the brain, making it a challenging condition to study and treat. The condition is characterized by tau protein building up in the brain and causes a wide range of problems in thinking, understanding, impulse control, and more. Recent NIH-funded research shows that, alarmingly, (https://www.nih.gov/news-events/nih-research-matters/chronic-traumatic-encephalopathy-young-athletes) even young, amateur players of contact and collision sports can have CTE, underscoring the urgency of finding ways to understand, diagnose, and treat CTE.1

New findings published in the journal Neurology show that increased presence of certain brain lesions that are visible on MRI scans may be related to other brain changes in former football players. The study describes a new way to capture and analyze the long-term impacts of repeated head injuries, which could have implications for understanding signs of CTE. 2

The study analyzes data from the (http://diagnosecte.com/) Diagnose CTE Research Project, an NIH-supported effort to develop methods for diagnosing CTE during life and to examine other potential risk factors for the degenerative brain condition. It involves 120 former professional football players and 60 former college football players with an average age of 57. For comparison, it also includes 60 men with an average age of 59 who had no symptoms, did not play football, and had no history of head trauma or concussion.

The new findings link some of the downstream risks of repetitive head impacts to injuries in white matter, the brain’s deeper tissue. Known as white matter hyperintensities (WMH), these injuries show up on MRI scans as easy-to-see bright spots.

Earlier studies had shown that athletes who had experienced repetitive head impacts had an unusual amount of WMH on their brain scans. Those markers, which also show up more as people age normally, are associated with an increased risk for stroke, cognitive decline, dementia and death. In the new study, researchers including (https://www.bu.edu/cte/profile/michael-alosco/) Michael Alosco, Boston University Chobanian & Avedisian School of Medicine, wanted to learn more about WMH and their relationship to other signs of brain trouble seen in former football players.

All the study’s volunteers had brain scans and lumbar punctures to collect cerebrospinal fluid in search of underlying signs or biomarkers of neurodegenerative disease and white matter changes. In the former football players, the researchers found more evidence of WMH. As expected, those with an elevated burden of WMH were more likely to have more risk factors for stroke—such as high blood pressure, hypertension, high cholesterol, and diabetes—but this association was 11 times stronger in former football players than in non-football players. More WMH was also associated with increased concentrations of tau protein in cerebrospinal fluid, and this connection was twice as strong in the football players vs. non-football players. Other signs of functional breakdown in the brain’s white matter were more apparent in participants with increased WMH, and this connection was nearly quadrupled in the former football players.

These latest results don’t prove that WMH from repetitive head impacts cause the other troubling brain changes seen in football players or others who go on to develop CTE. But they do highlight an intriguing association that may aid the further study and diagnosis of repetitive head impacts and CTE, with potentially important implications for understanding—and perhaps ultimately averting—their long-term consequences for brain health.

References:

[1] AC McKee, et al. Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts. JAMA Neurology. DOI:10.1001/jamaneurol.2023.2907 (2023).

[2] MT Ly, et al. (https://pubmed.ncbi.nlm.nih.gov/38165330/) Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players. Neurology. DOI: 10.1212/WNL.0000000000208030 (2024).

NIH Support: National Institute of Neurological Disorders and Stroke, National Institute on Aging and the National Center for Advancing Translational Sciences

(https://directorsblog.nih.gov/2024/01/11/a-new-target-to-improve-the-health-and-lives-of-childhood-cancer-survivors-diabetes-prevention/) A New Target to Improve the Health and Lives of Childhood Cancer Survivors: Diabetes Prevention
Jan 11th 2024, 14:00

Researchers found that prediabetes and diabetes are highly prevalent in survivors of childhood cancer. Credit Donny Bliss/NIH. Modified from (https://pubmed.ncbi.nlm.nih.gov/?term=38091552#:~:text=Conclusion%3A%20Prediabetes%20is%20highly%20prevalent,future%20cardiovascular%20and%20kidney%20complications.) SB Dixon, et al.

Before joining NIH, I conducted research on how inflammation drives colon cancer. I eventually led a trial to see if certain anti-inflammatory drugs could prevent the colon polyps that can can turn into cancer. The drugs worked; however, they also increased the risk of strokes and heart attacks, so they were not safe for people at high risk of cardiovascular disease.

The trial gave us valuable insight about the risks of these drugs and serves as an example of how clinicians and researchers must consider the needs of the whole patient rather than focusing on one organ system or disease. We have to recognize how certain interventions might improve one health issue but exacerbate another. This is especially important in adult survivors of childhood cancer. We know this population—about 500,000 people living in the U.S. according to 2020 estimates from the National Cancer Institute—faces an increased risk of developing chronic health conditions, including (https://www.niddk.nih.gov/health-information/diabetes) diabetes.

NIH supports numerous researchers working to understand better the health outcomes in childhood cancer survivors. One team at St. Jude Children’s Research Hospital in Memphis has been following more than 3,500 adults who had been diagnosed with childhood cancer. Known as the (https://sjlife.stjude.org/) St. Jude LIFE cohort, the participants undergo regular health screenings and researchers use the information to determine the prevalence and predictors of health issues and to identify interventions to reduce risks.

A new analysis published in the Journal of Clinical Oncology1 shows that (https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance) prediabetes is highly prevalent in the St. Jude LIFE cohort: about one in every three survivors in the study had prediabetes by a median age of 30, compared to about one in five similarly aged adults without a cancer history. Prediabetes means that a person has higher than normal blood sugar levels but not high enough for a diagnosis of diabetes. Without intervention, many people with prediabetes will later develop diabetes.

By the time survivors in the study entered their 40s, more than half of them had prediabetes or diabetes, putting their future health at more risk compared to the general population. While these findings aren’t good news, they suggest that efforts to detect prediabetes and encourage lifestyle or treatment interventions before survivors go on to have more serious health complications can ensure that more people will live longer, healthier lives.

The research team, led by (https://www.stjude.org/directory/d/stephanie-dixon.html) Stephanie Dixon, found that among 695 survivors with prediabetes who were followed over time, 10 percent progressed to diabetes within five years. The researchers also noted an association between radiation exposure to the pancreas and increased risk of prediabetes and diabetes. The pancreas produces insulin, and people are diagnosed with diabetes when the pancreas does not produce enough insulin to keep up with demand.

Their findings further suggest that, compared to survivors with normal blood sugar levels, those with prediabetes also had higher risk for future heart attack and chronic kidney disease. Those who progressed to diabetes also had more risk for developing stroke or cardiomyopathy (a condition where the heart pumps inefficiently and can lead to heart failure), in the future.

In the general population, prediabetes can be successfully managed through lifestyle changes, such as a healthy diet and exercise, as well as medication to prevent progression to diabetes and related health conditions. While this study is only a first step in identifying the consequences of prediabetes in survivors, it suggests that efforts to identify prediabetes and offer counseling on the importance of diabetes prevention may help more survivors of childhood cancers live long and healthy lives.

References:

[1] SB Dixon, et al. (https://pubmed.ncbi.nlm.nih.gov/?term=38091552#:~:text=Conclusion%3A%20Prediabetes%20is%20highly%20prevalent,future%20cardiovascular%20and%20kidney%20complications.) Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort. Journal of Clinical Oncology DOI: 10.1200/JCO.23.01005 (2023).

NIH Support: National Cancer Institute

(https://directorsblog.nih.gov/2024/01/04/uncovering-disease-driving-events-that-lead-to-type-2-diabetes/) Uncovering Disease-Driving Events that Lead to Type 2 Diabetes
Jan 4th 2024, 10:30

Researchers found lower levels of the protein RFX6 led to beta cells in the pancreas releasing less insulin. Lower RFX6 levels also led to structural changes in the DNA, specifically in sites that have known links to diabetes risk. Credit Donny Bliss/NIH

Nearly 35 million people in communities across the U.S. have (https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/type-2-diabetes#:~:text=Insulin%2C%20a%20hormone%20made%20by,not%20enough%20reaches%20your%20cells.) type 2 diabetes (T2D), putting them at increased risk for a wide range of serious health complications, including vision loss, kidney failure, heart disease, stroke, and premature death.1 While we know a lot about the lifestyle and genetic factors that influence diabetes risk and steps that can help prevent or control it, there’s still a lot to learn about the precise early events in the body that drive this disease.

When you have T2D, the insulin-producing beta cells in your pancreas don’t release insulin in the way that they should. As a result, blood sugar doesn’t enter your cells, and its levels in the bloodstream go up. What’s less clear is exactly what happens to cause beta cells and the cell clusters where they’re found (called islets) to malfunction in the first place. However, I’m encouraged by some new NIH-supported research in Nature that used various large datasets to identify key signatures of islet dysfunction in people with T2D.2

Earlier studies have linked about 400 sites in the human genome to an increased risk for T2D. But most of them—more than 9 in 10—are primarily in noncoding stretches of DNA that control genes. As a result, it’s been hard to figure out exactly how those genetic variants that increase risk in the general population lead to the changes in individuals who go on to develop T2D.

In the new study, a team led by (https://www.powersbrissovaresearch.org/) Marcela Brissova and Alvin C. Powers, Vanderbilt University Medical Center, Nashville, and (http://theparkerlab.org/) Stephen C.J. Parker, University of Michigan, Ann Arbor, used sophisticated analytic approaches to study changes within pancreatic tissues and islets taken from donors who’d had early-stage T2D at the time of their death. They included tissues from donors without T2D to serve as a comparison.

To get a better understanding, they looked at the tissues in multiple ways, studying differences in their basic physiology, gene activity, and cellular-level structures. By integrating data on these observed differences with other types of data from prior studies, they showed that impaired function of beta cells is a hallmark of early T2D, reinforcing prior evidence. Other pancreatic islet cell types appeared mostly unchanged.  

Their studies also showed that alterations in a particular gene network are key in early-stage T2D. The network, controlled by a protein called RFX6, cause pancreatic beta cells to malfunction. The researchers performed additional studies that showed lowering RFX6 levels led beta cells to secrete less insulin. Lower RFX6 levels also led to structural changes in the DNA, specifically in sites that have known links to diabetes risk. They expanded this finding by doing a population-scale genetic analysis. Using genetic information for more than 500,000 volunteers available in the UK biobank, they showed a causal link between lower levels of RFX6 and T2D.

Further study is needed to understand what’s behind the initial changes in RFX6. The researchers also want to explore further whether RFX6 might be a promising target for new treatments to prevent or reverse early-stage molecular and functional defects in the beta cell that underlie T2D. The researchers note that they have made all the data publicly available through user-friendly and interactive web portals, in hopes it will lead to more answers for the millions already affected by T2D and so many others who may be at risk.

References:

[1] (https://www.cdc.gov/diabetes/basics/type2.html#:~:text=About%2038%20million%20Americans%20have,adults%20are%20also%20developing%20it) Type 2 Diabetes. CDC. 

[2] JT Walker, DC Saunders, V Rai, et al. (https://pubmed.ncbi.nlm.nih.gov/38049589/) Genetic risk converges on regulatory networks mediating early type 2 diabetes. Nature. DOI: 10.1038/s41586-023-06693-2 (2023).

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of General Medical Sciences

(https://directorsblog.nih.gov/2023/12/19/turning-discoveries-into-health-for-all/) Turning Discoveries into Health for All
Dec 19th 2023, 09:00

Health and Human Services Secretary Xavier Becerra (left) swears in Monica M. Bertagnolli, M.D., (right) as the 17th Director of the National Institutes of Health. Dr. Bertagnolli’s husband, Alex Dannenberg, (center) also attended. Credit: Chia-Chi Charlie Chang, NIH

Greetings, blog readers! I’m Dr. Monica Bertagnolli, and I’m honored to be serving as the 17th Director of the National Institutes of Health. I’m excited to continue the NIH Director’s Blog to share with you the exciting discoveries and fascinating research conducted here at NIH and at the organizations we support in the U.S. and around the world. But before we start diving into the latest advances, I wanted to share a bit about myself and what I’m looking forward to as NIH Director.

I spent most of my career caring for people with cancer as a surgical oncologist and researcher before joining NIH last year as Director of the National Cancer Institute. While I miss the operating room (although I couldn’t stay away for long—more about that in a forthcoming blog!) and the opportunity to work with patients every day, I’m eager to serve the public in my new role as NIH Director.

When I was growing up, my family raised sheep and cattle on a ranch at the base of the Wind River Mountains in Wyoming. I know the health challenges that come with living in a rural area: Not everyone has access to an academic medical center and clinical studies, and managing the logistics of routine and preventive check-ups can be difficult. Unfortunately, many of our research advances are not reaching enough people in these areas.

As a (https://www.cancer.gov/news-events/press-releases/2022/nci-director-monica-bertagnolli-breast-cancer-diagnosis) cancer (https://www.cancer.gov/news-events/press-releases/2022/nci-director-monica-bertagnolli-breast-cancer-diagnosis) survivor, I am keenly aware that I’ve been fortunate to have access to excellent care, which has been directly informed by NIH-funded research over the past five decades. I know the transformative power of research to save lives, but from my experience as a clinician, I know that it is not always possible for people to receive the care that they need due to financial, geographic, or cultural barriers.  It is unacceptable for the benefits of NIH-funded biomedical research to be available to some but not all.  

That’s why one of my goals as NIH Director is to ensure the biomedical research enterprise and its discoveries—from basic to clinical research—are more inclusive and accessible to people from all walks of life, including rural areas. Income, age, race, ethnicity, geographic location, and disability status should not be barriers to participating in research or to benefitting from research advances. By meeting people where they are and engaging more communities as our research partners, I believe we can also make significant progress in rebuilding trust in science across the country.

Right now, we have an unprecedented opportunity to embrace and increase access to innovation: Our knowledge and technology have developed to the point that we should be able to deliver evidence-based, data-driven health care to everyone. This is an exciting time for science, and I can’t wait to share more with you in the weeks and months to come.

(https://directorsblog.nih.gov/2023/12/08/experiencing-the-neural-symphony-underlying-memory-through-a-blend-of-science-and-art/) Experiencing the Neural Symphony Underlying Memory through a Blend of Science and Art
Dec 8th 2023, 13:00

Ever wonder how you’re able to remember life events that happened days, months, or even years ago? You have your hippocampus to thank. This essential area in the brain relies on intense and highly synchronized patterns of activity that aren’t found anywhere else in the brain. They’re called “sharp-wave ripples.”

These dynamic ripples have been likened to the brain version of an instant replay, appearing most commonly during rest after a notable experience. And, now, the top video winner in this year’s (https://braininitiative.nih.gov/) Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative’s annual (https://braininitiative.nih.gov/news-events/show-us-your-brains-photo-video-contest) Show Us Your BRAINs! Photo and Video Contest allows you to witness the “chatter” that those ripples set off in other neurons. The details of this chatter determine just how durable a particular memory is in ways neuroscientists are still working hard to understand.

Neuroscientist Saman Abbaspoor in the lab of Kari Hoffman at Vanderbilt University, Nashville, in collaboration with Tyler Sloan from the Montreal-based Quorumetrix Studio, sets the stage in the winning video by showing an electrode or probe implanted in the brain that can reach the hippocampus. This device allows the Hoffman team to wirelessly record neural activity in different layers of the hippocampus as the animal either rests or moves freely about.

In the scenes that follow, neurons (blue, cyan, and yellow) flash on and off. The colors highlight the fact that this brain area and the neurons within it aren’t all the same. Various types of neurons are found in the brain area’s different layers, some of which spark the activity you see, while others dampen it.

Hoffman explains that the specific shapes of individual cells pictured are realistic but also symbolic. While they didn’t trace the individual branches of neurons in the brain in their studies, they relied on information from previous anatomical studies, overlaying their intricate forms with flashing bursts of activity that come straight from their recorded data.

Sloan then added yet another layer of artistry to the experience with what he refers to as sonification, or the use of music to convey information about the dynamic and coordinated bursts of activity in those cells. At five seconds in, you hear the subtle flutter of a sharp-wave ripple. With each burst of active neural chatter that follows, you hear the dramatic plink of piano keys.

Together, their winning video creates a unique sensory experience that helps to explain what goes on during memory formation and recall in a way that words alone can’t adequately describe. Through their ongoing studies, Hoffman reports that they’ll continue delving even deeper into understanding these intricate dynamics and their implications for learning and memory. Ultimately, they also want to explore how brain ripples, and the neural chatter they set off, might be enhanced to make memory formation and recall even stronger.

References:

S Abbaspoor & KL Hoffman. (https://www.biorxiv.org/content/10.1101/2023.12.06.570369v1) State-dependent circuit dynamics of superficial and deep CA1 pyramidal cells in macaques. BioRxiv DOI: 10.1101/2023.12.06.570369 (2023). Please note that this article is a pre-print and has not been peer-reviewed.

NIH Support: The NIH BRAIN Initiative

This article was updated on Dec. 15, 2023 to reflect better the collaboration on the project among Abbaspoor, Hoffman and Sloan. 

(https://directorsblog.nih.gov/2023/11/28/the-amazing-brain-turning-conventional-wisdom-on-brain-anatomy-on-its-head/) The Amazing Brain: Turning Conventional Wisdom on Brain Anatomy on its Head
Nov 28th 2023, 09:00

Credit: Silas Busch, The University of Chicago

Silas Busch at the University of Chicago captured this slightly eerie scene, noting it reminded him of people shuffling through the dark of night. What you’re really seeing are some of the largest (https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-life-and-death-neuron) neurons in the mammalian brain, known as Purkinje cells. The photo won first place this year in the (https://braininitiative.nih.gov/) Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative’s annual (https://braininitiative.nih.gov/news-events/show-us-your-brains-photo-video-contest) Show Us Your BRAINs! Photo and Video Contest.

While humans have them, too, the Purkinje cells pictured here are in the brain of a mouse. The head-like shapes you see in the image are the so-called soma, or the neurons’ cell bodies. Extending downwards are the heavily branched dendrites, which act like large antennae, receiving thousands of inputs from the rest of the body.

One reason this picture is such a standout, explains Busch, is because of what you don’t see. You’ll notice that only a few cells are fluorescently labeled and therefore lit up in green, leaving the rest in shadows. As a result, it’s possible to trace the detailed branches of individual Purkinje cells and make out their intricate forms. As it turns out, this ability to trace Purkinje cells so precisely led Busch, who is a graduate student in Christian Hansel’s lab focused on the neurobiology of learning and memory, to a surprising discovery, which the pair recently reported in Science.1

Purkinje cells connect to nerve fibers that “climb up” from the brain stem, which connects your brain and spinal cord to help control breathing, heart rate, balance and more. Scientists thought that each Purkinje cell received only one of these climbing fibers from the brain stem on its single primary branch.

However, after carefully tracing thousands of Purkinje cells in brain tissue from both mice and humans, the researchers have now shown that Purkinje cells and climbing fibers don’t always have a simple one-to-one relationship. In fact, Busch and Hansel found more than 95 percent of human Purkinje cells have multiple primary branches, not just one. In mice, that ratio is closer to 50 percent.

The researchers went on to show that mouse Purkinje cells with multiple primary branches often also receive multiple climbing fibers. The discovery rewrites the textbook idea of how Purkinje cells in the brain and climbing fibers from the brainstem are anatomically arranged.

Not surprisingly, those extra connections in the cerebellum (located in the back of the brain) also have important functional implications. When Purkinje cells have just one climbing fiber input, the new study shows, the whole cell receives each signal equally and responds accordingly. But, in cells with multiple climbing fiber inputs, the researchers could detect differences across a single cell depending on which primary branch received an input.

What this means is that Purkinje cells in the brain have much more computational power than had been appreciated. That extra brain power has important implications for understanding how brain circuits can adapt and respond to changes outside the body that now warrant further study. The new findings may have implications also for understanding the role of these Purkinje cell connections in some neurological and developmental disorders, including (https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd) autism2 and a movement disorder known as (https://www.ninds.nih.gov/health-information/disorders/ataxia-and-cerebellar-or-spinocerebellar-degeneration) cerebellar ataxia.

As they say, a picture is worth a thousand words. And this winning image comes as a reminder that we still have more to learn from careful study of basic brain anatomy, with important implications for human health and disease. 

References:

[1] SE Busch and C Hansel. (https://pubmed.ncbi.nlm.nih.gov/37499000/) Climbing fiber multi-innervation of mouse Purkinje dendrites with arborization common to human. Science. DOI: 10.1126/science.adi1024. (2023).

[2] DH Simmons et al. (https://pubmed.ncbi.nlm.nih.gov/36324646/) Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism. Biological Psychiatry: Global Open Science. DOI: 10.1016/j.bpsgos.2021.09.004. (2021).

(https://directorsblog.nih.gov/2023/11/14/metabolomics-a-new-approach-to-understanding-glaucoma/) Metabolomics: A New Approach to Understanding Glaucoma
Nov 14th 2023, 09:00

Patients with high levels of triglycerides and diglycerides in blood samples were more likely to develop glaucoma. Credit Donny Bliss/NIH

(https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/glaucoma) Glaucoma remains one of the most common causes of vision loss and blindness in the U.S. and much of the world, disproportionately affecting older people, African Americans, and Hispanics and Latinos. Early signs of glaucoma can vary, from eye pressure to changes in the appearance of the optic nerve, and the disease can progress for years undetected while causing irreversible vision loss. More research is needed to understand the complex processes that underpin how glaucoma develops and progresses. If detected early enough, doctors can intervene and stop or slow its progression, thus preventing or minimizing vision loss.

While more than 120 genetic factors have been linked to glaucoma, these genes account for less than 10% of glaucoma cases. Scientists are exploring other ways to predict glaucoma, including studying metabolites to see if they hold any clues. These small molecules are produced by metabolism, including the breakdown of nutrients when we digest food or byproducts from the medicine we take. Identifying at-risk individuals based on their metabolic profile might present an opportunity to intercept disease before vision loss.

Researchers already use metabolites as biomarkers or indicators to help diagnose disease or assess disease risk. There’s a standard blood test called a comprehensive metabolic blood panel that doctors use to measure levels of metabolites circulating in your blood—sugars like glucose, minerals such as calcium, and proteins such as creatinine.

Your metabolome is the complete set of metabolites not in just your blood but in your entire body. National Eye Institute-funded researchers led by Louis Pasquale, Icahn School of Medicine at Mount Sinai, New York, in collaboration with Oana A. Zeleznik and Jae Hee Kang of Brigham and Women’s Hospital, Boston, recently explored 369 blood metabolites in relation to glaucoma in a large study.1

The research team examined blood that had been stored frozen from two long-term studies of health professionals: the Nurses’ Health Studies and the Health Professionals’ Follow-Up Study. They compared about 600 participants who had developed glaucoma after study enrollment to a group of similar participants who didn’t. On average, the participants who developed glaucoma did so about 10 years after their initial blood draw in the study.

The researchers found a particularly strong association between glaucoma and two classes of lipids (fats): triglycerides and diglycerides. Patients with elevated triglycerides and diglycerides were more likely to develop glaucoma, and the association was strongest in a subtype of glaucoma that causes early loss of central vision. They confirmed their findings in a cross-sectional analysis of data from the (https://www.ukbiobank.ac.uk/) UK Biobank.

High levels of triglycerides have been linked to a variety of health problems, notably heart disease and stroke. The good news is that effective treatments to control triglyceride levels already exist. Statin drugs, for example, lower blood lipid levels. While studies looking at statin use and glaucoma risk have shown mixed results, we may learn that specific subtypes of glaucoma can be effectively controlled with statins. More research is needed to know if existing drugs might prevent glaucoma.

Pasquale’s work adds to a growing body of evidence that links health status to metabolism. Similar associations have been made between various metabolites and kidney cancer,2 pregnancy complications,3 type 2 diabetes,4 and Alzheimer’s disease.5 For researchers interested in exploring associations between metabolites and disease risk, the NIH Common Fund offers scientists a national and international repository for metabolomics data and metadata called the (https://www.metabolomicsworkbench.org/databases/metabolitedatabase.php) Metabolomics Workbench Metabolite Database, which contained more than 167,000 entries in 2022.

These findings and others offer the potential to prevent more and treat less. We urge anyone in an at-risk group, including people with a family history of glaucoma, to get regular, comprehensive eye exams.

References:

[1] OA Zeleznik, et al. (https://pubmed.ncbi.nlm.nih.gov/37208353/) Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank. Nature Communications DOI:10.1038/s41467-023-38466-x (2023)

[2] OO Bifarin, et al. (https://pubmed.ncbi.nlm.nih.gov/34944874/) Urine-Based Metabolomics and Machine Learning Reveals Metabolites Associated with Renal Cell Carcinoma Stage. Cancers (Basel) DOI:10.3390/cancers13246253 (2021)

[3] EW Harville, et al. (https://pubmed.ncbi.nlm.nih.gov/33568690/) Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study. Scientific Reports DOI:10.1038/s41598-021-82804-1 (2021)

[4] Nightingale Health Biobank Collaborative Group, et al. (https://www.medrxiv.org/content/10.1101/2023.06.09.23291213v1) Metabolomic and genomic prediction of common diseases in 477,706 participants in three national biobanks. medRxiv DOI: 10.1101/2023.06.09.23291213 (2023). *note this article is a pre-print and is not peer-reviewed

[5] DK Barupal, et al. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732667/) Sets of coregulated serum lipids are associated with Alzheimer’s disease pathophysiology. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. DOI:10.1016/j.dadm.2019.07.002 (2019)

NIH Support: National Eye Institute, National Cancer Institute

Editor’s note: This blog post was updated on Jan. 18, 2024, to include Oana A. Zeleznik as one of the collaborators.

(https://directorsblog.nih.gov/2023/11/09/reflecting-on-two-years-of-discovery-and-looking-ahead-to-new-nih-leadership/) Reflecting on Two Years of Discovery and Looking Ahead to New NIH Leadership
Nov 9th 2023, 17:00

Dr. Larry Tabak in his office at the National Institutes of Health. Credit: NIH

As I transition from my role as the Acting NIH Director, I’d like to thank you, the readers, for visiting the NIH Director’s Blog ever since I took the helm 22 months ago. From Long COVID to the opioid overdose epidemic to Alzheimer’s disease—we’ve covered a range of diseases and conditions, scientific advances, and programs. You were able to read about such a broad spectrum of science thanks in large part to the many Institute Directors at NIH who authored guest posts. I hope the blog has helped you learn more about what NIH does and the many ways that biomedical research impacts human health.

A key focus of my career as both a scientific investigator and administrative leader has been supporting trainees and finding new ways to cultivate and expand the next generation of researchers. In my many discussions with young investigators, I’ve often reminded them that they should not be afraid to fail. To the students and early-stage scientists who have visited this site: I hope these stories of discovery—often the result of earlier failures—have provided some insight and inspiration as you move through your scientific career or consider starting one.

I’d also like to thank the many people—employees, government and private partners, patients, scientists, advocates, and other members of the public—who have reached out with messages of support, and sometimes with messages of criticism. Both have helped inform the decisions I needed to make to fulfill the NIH mission.

In closing, I congratulate Dr. Monica Bertagnolli as she takes the helm as the next permanent NIH director. Dr. Bertagnolli—an outstanding physician scientist—is a strong leader who will bring fresh, bold new ideas to NIH and the biomedical research enterprise. I know she’ll be in good hands thanks to the outstanding staff across NIH and the leadership in the Department of Health and Human Services. I look forward to supporting her efforts and continuing to ensure that NIH research optimizes health for all people.


(https://directorsblog.nih.gov/2023/11/03/senator-ben-cardin-visits-nih/) Senator Ben Cardin Visits NIH
Nov 3rd 2023, 08:46

I was pleased to welcome Senator Ben Cardin to NIH last week for a lab tour and an update on NIH’s progress in minority health research. To my left is Dr. Tara Schwetz, NIH Acting Principal Deputy Director and Dr. Gary Gibbons, Director of the National Heart, Lung and Blood Institute. To my right is Dr. Monica Webb Hooper, Deputy Director of the National Institute on Minority Health and Health Disparities, and Dr. Gregory G. Germino, Deputy Director of the National Institute of Diabetes and Digestive and Kidney Diseases.  Credit: Chiachi Chang, NIH

(https://directorsblog.nih.gov/2023/11/01/first-lady-dr-jill-biden-visits-nih/) First Lady Dr. Jill Biden Visits NIH
Nov 1st 2023, 14:45

(https://directorsblog.nih.gov/wp-content/uploads/2023/11/First-Lady-Dr-Biden-Visits-NIH.jpg) It was an honor to welcome the First Lady of the United States Dr. Jill Biden and Ms. Jodie Haydon of Australia to NIH last week. We shared NIH’s progress in pediatric cancer research during a visit to the NIH Clinical Center. Also pictured (left to right): Children’s Inn CEO MS. Jennie Luca, Clinical Center CEO Dr. James Gilman and NCI Director Dr. Monica Bertagnolli. 
Credit: Chiachi Chang, NIH

(https://directorsblog.nih.gov/2023/10/31/how-double-stranded-rna-protects-the-brain-against-infection-while-making-damaging-neuroinflammation-more-likely/) How Double-Stranded RNA Protects the Brain Against Infection While Making Damaging Neuroinflammation More Likely
Oct 31st 2023, 12:00

A neuron (white) with double-stranded RNA (yellow). Credit: Donny Bliss, NIH.

When you get a run-of-the-mill viral infection, after a few days of symptoms your immune system typically fends off the bug, and you’ll make a full recovery. In rare cases, a virus can (https://www.ninds.nih.gov/health-information/disorders/encephalitis#:~:text=Infections%20and%20other%20disorders%20affecting,show%20mild%20flu-like%20symptoms.) infect the brain. This can lead to much bigger problems, including cognitive impairments known as “brain fog,” other neuropsychiatric symptoms, potentially irreversible brain damage, or even death. For this reason, the brain, more than other parts of the body, relies heavily on immune responses that can control viral infections immediately.

Now some intriguing findings from an NIH-funded team reported in Science Immunology help to explain how the brain is protected against infections.1 However, the findings also highlight a serious downside: these same mechanisms that protect the brain also leave it especially vulnerable to damaging levels of neuroinflammation.

The new findings may help to explain what goes on in the brains of people with a wide range of neurodegenerative conditions, including (https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als) amyotrophic lateral sclerosis (ALS) and (https://www.nia.nih.gov/health/topics/alzheimers-and-dementia) Alzheimer’s disease. They also point to promising targets for developing treatments that might turn inflammatory immune responses in the brain up or down, as desired, to treat these and other serious conditions. 

How does it work? The key is double-stranded RNA (dsRNA).

(https://www.genome.gov/genetics-glossary/RNA-Ribonucleic-Acid) RNA molecules are readouts of genetic information in DNA that carry instructions for building the proteins that carry out various cell functions. RNA molecules in our cells are most often in single-stranded or short dsRNA form. In contrast, lengthy dsRNAs are a hallmark of viruses. When a virus invades our cells, our immune system’s first line of defense can sense those long viral dsRNAs and trigger a response.

But it turns out that dsRNAs aren’t unique to viruses, as the new study highlights. The researchers, led by Tyler Dorrity and Heegwon Shin, both members of Hachung Chung’s lab at Columbia University Irving Medical Center, New York, found that human neurons—even when they’re normal and healthy—also have exceptionally high levels of long dsRNAs.

Their lab studies in cells and tissues show that these dsRNAs in neurons can trigger an inflammatory immune response just as they do in viruses. By manipulating neurons in a way that cut back on the number of dsRNAs, they found they could lower the innate immune response. However, cells with fewer dsRNAs also showed greater susceptibility to infection with Zika viruses and herpes simplex virus, which can produce a form of viral (https://www.ninds.nih.gov/health-information/disorders/encephalitis#:~:text=Infections%20and%20other%20disorders%20affecting,show%20mild%20flu-like%20symptoms.) encephalitis.

The researchers also knew from earlier studies that people with a rare, inherited condition called (https://www.ninds.nih.gov/health-information/disorders/aicardi-goutieres-syndrome) Aicardi-Goutières syndrome (AGS), which primarily affects the brain and immune system, carry a mutation that causes their cells to lack an enzyme needed to edit dsRNAs. As a result, neurons carrying this mutation have so many dsRNAs that it is toxic.

They went on to show that they could shift this dynamic by altering levels of two other proteins that bind RNA. The proteins normally encourage dsRNA formation in the brain. When the researchers deleted these RNA-binding proteins from the AGS neurons, those neurons made fewer long dsRNAs, which in turn protected them from the inflammatory immune responses and allowed them to survive longer. As expected, however, those cells also were more susceptible to viral infection.

The findings show how this tricky balance between susceptibility to infection and inflammation in the brain works in both health and disease. It also leads to the tantalizing suggestion that treatments targeting these various players or others in the same pathways may offer new ways of treating brain infections or neuroinflammatory conditions, by boosting or dampening dsRNA levels and the associated immune responses. As a next step, the researchers report that they’re pursuing studies to explore the role of dsRNA-triggered immune responses in ALS and Alzheimer’s, as well as in neuropsychiatric symptoms sometimes seen in people with (https://www.niams.nih.gov/health-topics/lupus) lupus.

References:

[1] TJ Dorrity TJ, et al. (https://pubmed.ncbi.nlm.nih.gov/37862432/) Long 3’UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation. Science Immunology DOI: 10.1126/sciimmunol.adg2979 (2023).

NIH Support: National Institute of Neurological Disorders and Stroke, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences

(https://directorsblog.nih.gov/2023/10/24/brain-atlas-paves-the-way-for-new-understanding-of-how-the-brain-functions/) Brain Atlas Paves the Way for New Understanding of How the Brain Functions
Oct 24th 2023, 09:00

Neurons. Credit: Leterrier, NeuroCyto Lab, INP, Marseille, France

When NIH launched (https://braininitiative.nih.gov) The BRAIN Initiative® a decade ago, one of many ambitious goals was to develop innovative technologies for profiling single cells to create an open-access reference atlas cataloguing the human brain’s many parts. The ultimate goal wasn’t to produce a single, static reference map, but rather to capture a dynamic view of how the brain’s many cells of varied types are wired to work together in the healthy brain and how this picture may shift in those with neurological and mental health disorders.

So I’m now thrilled to report the publication of an impressive collection of work from hundreds of scientists in the (https://braininitiative.nih.gov/research/tools-and-technologies-brain-cells-and-circuits/brain-initiative-cell-census-network) BRAIN Initiative Cell Census Network (BICCN), detailed in more than 20 papers in Science, Science Advances, and Science Translational Medicine.1 Among many revelations, this unprecedented, international effort has characterized more than 3,000 human brain cell types. To put this into some perspective, consider that the human lung contains 61 cell types.2 The work has also begun to uncover normal variation in the brains of individual people, some of the features that distinguish various disease states, and distinctions among key parts of the human brain and those of our closely related primate cousins.

Of course, it’s not possible to do justice to this remarkable body of work or its many implications in the space of a single blog post. But to give you an idea of what’s been accomplished, some of these studies detail the primary effort to produce a comprehensive brain atlas, including defining the brain’s many cell types along with their underlying gene activity and the chemical modifications that turn gene activity up or down.3,4,5

Other studies in this collection take a deep dive into more specific brain areas. For instance, to capture normal variations among people, a team including Nelson Johansen, University of California, Davis, profiled cells in the neocortex—the outermost portion of the brain that’s responsible for many complex human behaviors.6 Overall, the work revealed a highly consistent cellular makeup from one person to the next. But it also highlighted considerable variation in gene activity, some of which could be explained by differences in age, sex and health. However, much of the observed variation remains unexplained, opening the door to more investigations to understand the meaning behind such brain differences and their role in making each of us who we are.

Yang Li, now at Washington University in St. Louis, and his colleagues analyzed 1.1 million cells from 42 distinct brain areas in samples from three adults.4 They explored various cell types with potentially important roles in neuropsychiatric disorders and were able to pinpoint specific cell types, genes and genetic switches that may contribute to the development of certain traits and disorders, including bipolar disorder, depression and schizophrenia.

Yet another report by Nikolas Jorstad, Allen Institute, Seattle, and colleagues delves into essential questions about what makes us human as compared to other primates like chimpanzees.7 Their comparisons of gene activity at the single-cell level in a specific area of the brain show that humans and other primates have largely the same brain cell types, but genes are activated differently in specific cell types in humans as compared to other primates. Those differentially expressed genes in humans often were found in portions of the genome that show evidence of rapid change over evolutionary time, suggesting that they play important roles in human brain function in ways that have yet to be fully explained.

All the data represented in this work has been made publicly accessible (https://nemoarchive.org/) online for further study. Meanwhile, the effort to build a more finely detailed picture of even more brain cell types and, with it, a more complete understanding of human brain circuitry and how it can go awry continues in the (https://braininitiative.nih.gov/research/tools-technologies-brain-cells-circuits/brain-initiative-cell-atlas-network) BRAIN Initiative Cell Atlas Network (BICAN). As impressive as this latest installment is—in our quest to understand the human brain, brain disorders, and their treatment—we have much to look forward to in the years ahead.

References:

A list of all the papers part of the brain atlas research is available here: (https://www.science.org/collections/brain-cell-census) https://www.science.org/collections/brain-cell-census.

[1] M Maroso. (https://www.science.org/doi/full/10.1126/science.adl0913) A quest into the human brain. Science DOI: 10.1126/science.adl0913 (2023).                                                  

[2] L Sikkema, et al. (https://pubmed.ncbi.nlm.nih.gov/37291214/) An integrated cell atlas of the lung in health and disease. Nature Medicine DOI: 10.1038/s41591-023-02327-2 (2023).

[3] K Siletti, et al. (https://www.science.org/doi/full/10.1126/science.add7046) Transcriptomic diversity of cell types across the adult human brain. Science DOI: 10.1126/science.add7046 (2023).

[4] Y Li, et al. (https://www.science.org/doi/full/10.1126/science.adf7044) A comparative atlas of single-cell chromatin accessibility in the (https://www.science.org/doi/full/10.1126/science.adf7044) h(https://www.science.org/doi/full/10.1126/science.adf7044) uman brain. Science DOI: 10.1126/science.adf7044 (2023).

[5] W Tian, et al. (https://www.science.org/doi/full/10.1126/science.adf5357) Single-cell DNA methylation and 3D genome architecture in the human brain. Science DOI: 10.1126/science.adf5357 (2023).

[6] N Johansen, et al. (https://www.science.org/doi/full/10.1126/science.adf2359) Interindividual variation in human cortical cell type abundance and expression. Science DOI: 10.1126/science.adf2359 (2023).

[7] NL Jorstad, et al. (https://www.science.org/doi/full/10.1126/science.ade9516) Comparative transcriptomics reveals human-specific cortical features. Science DOI: 10.1126/science.ade9516 (2023).

NIH Support: (https://braininitiative.nih.gov/funding/funded-awards?field_fiscal_year_value=&field_program_target_id%5B240%5D=240&title=) Projects funded through the NIH BRAIN Initiative Cell Consensus Network

(https://directorsblog.nih.gov/2023/10/17/can-bioprinted-skin-substitutes-replace-traditional-grafts-for-treating-burn-injuries-and-other-serious-skin-wounds/) Can Bioprinted Skin Substitutes Replace Traditional Grafts for Treating Burn Injuries and Other Serious Skin Wounds?
Oct 17th 2023, 09:00

Artificial skin is printed by layering specific cell mixtures to mimic human skin: epidermis (top), dermis (middle) and hypodermis (bottom). Credit: Donny Bliss/NIH

Each year in the U.S., more than 500,000 people receive treatment for (https://www.nigms.nih.gov/education/fact-sheets/Pages/burns.aspx) burn injuries and other serious skin wounds.1 To close the most severe wounds with less scarring, doctors often must surgically remove skin from one part of a person’s body and use it to patch the injured site. However, this is an intensive process, and some burn patients with extensive skin loss do not have sufficient skin available for grafting. Scientists have been exploring ways to repair these serious skin wounds without skin graft surgery.

An NIH-funded team recently showed that bioprinted skin substitutes may serve as a promising alternative to traditional skin grafts in preclinical studies reported in Science Translational Medicine.2 The approach involves a portable skin bioprinter system that deposits multiple layers of skin directly into a wound. The recent findings add to evidence that bioprinting technology can successfully regenerate human-like skin to allow healing. While this approach has yet to be tested in people, it confirms that such technologies already can produce skin constructs with the complex structures and multiple cell types present in healthy human skin.

This latest work comes from a team led by (https://ctsi.wakehealth.edu/education-and-training/msrd/2020-winners/adam-jorgensen) Adam Jorgensen and (https://school.wakehealth.edu/faculty/a/anthony-atala) Anthony Atala at Wake Forest School of Medicine’s Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC. Members of the Atala lab and their colleagues had earlier shown it was possible to isolate two major skin cell types found in the skin’s outer (epidermis) and middle (dermis) layers from a small biopsy of healthy skin, expand the number of cells in the lab and then deliver the cells directly into an injury using a specially designed bioprinter.3 Using integrated imaging technology to scan a wound, computer software “prints” cells right into an injury, mimicking two of our skin’s three natural layers.

In the new study, Atala’s team has gone even further to construct skin substitutes that mimic the structure of human skin and that include six primary human skin cell types. They then used their bioprinter to produce skin constructs with all three layers found in healthy human skin: epidermis, dermis, and hypodermis.

To put their skin substitutes to the test, they first transplanted them into mice. Their studies showed that the bioprinted skin encouraged the rapid growth of new blood vessels and had other features of normal-looking, healthy skin. The researchers were able to confirm that their bioprinted skin implants successfully integrated into the animals’ regenerated skin to speed healing.

Studies in a pig model of wound healing added to evidence that such bioprinted implants can successfully repair full-thickness wounds, meaning those that extend through all three layers of skin. The bioprinted skin patches allowed for improved wound healing with less scarring. They also found that the bioprinted grafts encouraged activity in the skin from genes known to play important roles in wound healing.

It’s not yet clear if this approach will work as well in the clinic as it does in the lab. To make it feasible, the researchers note there’s a need for improved approaches to isolating and expanding the needed skin cell types. Nevertheless, these advances come as encouraging evidence that bioprinted skin substitutes could one day offer a promising alternative to traditional skin grafts with the capacity to help even more people with severe burns or other wounds.

References:

[1] (https://ameriburn.org/who-we-are/media/burn-incidence-fact-sheet/) Burn Incidence Fact Sheet. American Burn Association

[2] AM Jorgensen, et al. (https://pubmed.ncbi.nlm.nih.gov/37792956/) Multicellular bioprinted skin facilitates human-like skin architecture in vivo. Science Translational Medicine DOI: 10.1126/scitranslmed.adf7547 (2023).

[3] M Albanna, et al. (https://pubmed.ncbi.nlm.nih.gov/30755653/) In Situ Bioprinting of Autologous Skin Cells Accelerates Wound Healing of Extensive Excisional Full-Thickness Wounds. Scientific Reports DOI: 10.1038/s41598-018-38366-w (2019).

NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases

(https://directorsblog.nih.gov/2023/10/12/persistence-pays-off-recognizing-katalin-kariko-and-drew-weissman-the-2023-nobel-prize-winners-in-physiology-or-medicine/) Persistence Pays Off: Recognizing Katalin Karikó and Drew Weissman, the 2023 Nobel Prize Winners in Physiology or Medicine
Oct 12th 2023, 10:00

Karikó and Weissman discovered how to slightly modify mRNA to avoid an inflammatory response making the mRNA vaccines possible. Credit: Donny Bliss/NIH

Last week, (https://www.nobelprize.org/prizes/medicine/2023/press-release/) biochemist Katalin Karikó and immunologist Drew Weissman earned the Nobel Prize in Physiology or Medicine for their discoveries that enabled the development of effective messenger RNA (mRNA) vaccines against COVID-19. On behalf of the NIH community, I’d like to congratulate Karikó and Weissman and thank them for their persistence in pursuing their investigations. NIH is proud to have supported their seminal research, cited by the Nobel Assembly as key publications.1,2,3

While the lifesaving benefits of mRNA vaccines are now clearly realized, Karikó and Weissman’s breakthrough finding in 2005 was not fully appreciated at the time as to why it would be significant. However, their dogged dedication to gaining a better understanding of how RNA interacts with the immune system underscores the often-underappreciated importance of incremental research. Following where the science leads through step-by-step investigations often doesn’t appear to be flashy, but it can end up leading to major advances.

To best describe Karikó and Weissman’s discovery, I’ll first do a quick review of vaccine history. As many of you know, vaccines stimulate our immune systems to protect us from getting infected or from getting very sick from a specific pathogen. (https://www.who.int/news-room/spotlight/history-of-vaccination/a-brief-history-of-vaccination) Since the late 1700s, scientists have used (https://historyofvaccines.org/vaccines-101/what-do-vaccines-do/different-types-vaccines) various approaches to design effective vaccines. Some vaccines introduce a weakened or noninfectious version of a virus to the body, while others present only a small part of the virus, like a protein. The immune system detects the weak or partial virus and develops specialized defenses against it. These defenses work to protect us if we are ever exposed to the real virus.  

In the early 1990s, scientists began exploring a different approach to vaccines that involved delivering genetic material, or instructions, so the body’s own cells could make the virus proteins that stimulate an immune response.4,5 Because this approach eliminates the step of growing virus or virus protein in the laboratory—which can be difficult to do in very large quantities and can require a lot of time and money—it had potential, in theory, to be a faster and cheaper way to manufacture vaccines.

Scientists were exploring two types of vaccines as part of this new approach: DNA vaccines and messenger RNA (mRNA) vaccines. DNA vaccines deliver an encoded protein recipe that the cell first copies or transcribes before it starts making protein. For mRNA vaccines, the transcription process is done in the laboratory, and the vaccine delivers the “readable” instructions to the cell for making protein. However, mRNA was not immediately a practical vaccine approach due to several scientific hurdles, including that it caused inflammatory reactions that could be unhealthy for people.

Unfazed by the challenges, (https://www.nobelprize.org/prizes/medicine/2023/advanced-information/) Karikó and Weissman spent years pursuing research on RNA and the immune system. They had a brilliant idea that they turned into a significant discovery in 2005 when they proved that inserting subtle chemical modifications to lab-transcribed mRNA eliminated the unwanted inflammatory response.1 In later studies, the pair showed that these chemical modifications also increased protein production.2,3 Both discoveries would be critical to advancing the use of mRNA-based vaccines and therapies.

Earlier theories that mRNA could enable rapid vaccine development turned out to be true. By March 2020, (https://www.niaid.nih.gov/news-events/nih-clinical-trial-investigational-vaccine-covid-19-begins) the first clinical trial of an mRNA vaccine for COVID-19 had begun enrolling volunteers, and by December 2020, health care workers were receiving their first shots. This unprecedented timeline was only possible because of Karikó and Weissman’s decades of work, combined with the tireless efforts of many academic, industry and government scientists, including several from the (https://directorsblog.nih.gov/2020/12/22/celebrating-the-gift-of-covid-19-vaccines/) NIH intramural program.  Now, researchers are exploring how mRNA could be used in (https://www.niaid.nih.gov/news-events/clinical-trial-mrna-universal-influenza-vaccine-candidate-begins) vaccines for other infectious diseases and in (https://www.cancer.gov/news-events/cancer-currents-blog/2022/mrna-vaccines-to-treat-cancer) cancer vaccines.

As an investigator myself, I’m fascinated by how science continues to build on itself—a process that is done out of the public eye. Luckily every year, the Nobel Prize briefly illuminates for the larger public this long arc of scientific discovery. The Nobel Assembly’s recognition of Karikó and Weissman is a tribute to all scientists who do the painstaking work of trying to understand how things work. Many of the tools we have today to better prevent and treat diseases would not have been possible without the brilliance, tenacity and grit of researchers like Karikó and Weissman.

References:

K Karikó, et al. (https://pubmed.ncbi.nlm.nih.gov/16111635/) Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity DOI: 10.1016/j.immuni.2005.06.008 (2005).

K Karikó, et al. (https://pubmed.ncbi.nlm.nih.gov/18797453/) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Molecular Therapy DOI: 10.1038/mt.2008.200 (2008).

BR Anderson, et al. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943593/) Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Research DOI: 10.1093/nar/gkq347 (2010).

DC Tang, et al. (https://pubmed.ncbi.nlm.nih.gov/1545867/) Genetic immunization is a simple method for eliciting an immune response. Nature DOI: 10.1038/356152a0 (1992).

F Martinon, et al. (https://pubmed.ncbi.nlm.nih.gov/8325342/) Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European Journal of Immunology DOI: 10.1002/eji.1830230749 (1993).

NIH Support:

Katalin Karikó: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke

Drew Weissman: National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute

(https://directorsblog.nih.gov/2023/10/10/taking-a-deep-dive-into-the-alzheimers-brain-in-search-of-understanding-and-new-targets/) Taking a Deep Dive into the Alzheimer’s Brain in Search of Understanding and New Targets
Oct 10th 2023, 12:00

Researchers characterized gene activity at the single-cell level in more than 2 million cells from brain tissue. The findings detailed the molecular drivers of Alzheimer’s disease and which cell types in the brain are most likely to be affected. Credit: Donny Bliss/NIH

People living with Alzheimer’s disease experience a gradual erosion of memory and thinking skills until they can no longer carry out daily activities. Hallmarks of the disease include the buildup of plaques that collect between neurons, accumulations of tau protein inside neurons and weakening of neural connections. However, there’s still much to learn about what precisely happens in the Alzheimer’s brain and how the disorder’s devastating march might be slowed or even stopped. Alzheimer’s affects more than six million people in the United States and is the seventh leading cause of death among adults in the U.S., according to the (https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet) National Institute on Aging.

NIH-supported researchers recently published a trove of data in the journal Cell detailing the molecular drivers of Alzheimer’s disease and which cell types in the brain are most likely to be affected.1,2,3,4 The scientists, led by (https://tsailaboratory.mit.edu/li-huei-tsai/) Li-Huei Tsai and (http://compbio.mit.edu) Manolis Kellis, both at the Massachusetts Institute of Technology, Cambridge, MA, characterized gene activity at the (https://commonfund.nih.gov/singlecell) single-cell level in more than two million cells from postmortem brain tissue. They also assessed DNA damage and surveyed (https://www.genome.gov/about-genomics/fact-sheets/Epigenomics-Fact-Sheet) epigenetic changes in cells, which refers to chemical modifications to DNA that alter gene expression in the cell. The findings could help researchers pinpoint new targets for Alzheimer’s disease treatments.

In the first of four studies, the researchers examined 54 brain cell types in 427 brain samples from a (https://dss.niagads.org/cohorts/religious-orders-study-memory-and-aging-project-rosmap/) cohort of people with varying levels of cognitive impairment that has been followed since 1994.1 The MIT team generated an atlas of gene activity patterns within the brain’s prefrontal cortex, an important area for memory retrieval.

Their analyses in brain samples taken from people with Alzheimer’s dementia showed altered activity in genes involved in various functions. Additional findings showed that people with normal cognitive abilities with evidence of plaques in their brains had more neurons that inhibit or dampen activity in the prefrontal cortex compared to those with Alzheimer’s dementia. The finding suggests that the workings of inhibitory neurons may play an unexpectedly important role in maintaining cognitive resilience despite age-related changes, including the buildup of plaques. It’s one among many discoveries that now warrant further study.

In another report, the researchers compared brain tissues from 48 people without Alzheimer’s to 44 people with early- or late-stage Alzheimer’s.2 They developed a map of the various elements that regulate function within cells in the prefrontal cortex. By cross-referencing epigenomic and gene activity data, the researchers showed changes in many genes with known links to Alzheimer’s disease development and risk.

Their single-cell analysis also showed that these changes most often occur in microglia, which are immune cells that remove cellular waste products from the brain. At the same time, every cell type they studied showed a breakdown over time in the cells’ normal epigenomic patterning, a process that may cause a cell to behave differently as it loses essential aspects of its original identity and function.

In a third report, the researchers looked even deeper into gene activity within the brain’s waste-clearing microglia.3 Based on the activity of hundreds of genes, they were able to define a dozen distinct microglia “states.” They also showed that more microglia enter an inflammatory state in the Alzheimer’s brain compared to a healthy human brain. Fewer microglia in the Alzheimer’s brain were in a healthy, balanced state as well. The findings suggest that treatments that target microglia to reduce inflammation and promote balance may hold promise for treating Alzheimer’s disease.

The fourth and final report zeroed in on DNA damage, inspired in part by earlier findings suggesting greater damage within neurons even before Alzheimer’s symptoms appear.4 In fact, breaks in DNA occur as part of the normal process of forming new memories. But those breaks in the healthy brain are quickly repaired as the brain makes new connections.

The researchers studied postmortem brain tissue samples and found that, over time in the Alzheimer’s brain, the damage exceeds the brain’s ability to repair it. As a result, attempts to put the DNA back together leads to a patchwork of mistakes, including rearrangements in the DNA and fusions as separate genes are merged. Such changes appear to arise especially in genes that control neural connections, which may contribute to the signs and symptoms of Alzheimer’s.

The researchers say they now plan to apply artificial intelligence and other analytic tools to learn even more about Alzheimer’s disease from this trove of data. To speed progress even more, they’ve made all the data freely available online to the research community, where it promises to yield many more fundamentally important discoveries about the precise underpinnings of Alzheimer’s disease in the brain and new ways to intervene in Alzheimer’s dementia.

References:

[1] Mathys H, et al. (https://pubmed.ncbi.nlm.nih.gov/37774677/) Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology. Cell. DOI: 10.1016/j.cell.2023.08.039. (2023).

[2] Xiong X, et al. (https://pubmed.ncbi.nlm.nih.gov/37774680/) Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion. Cell. DOI: 10.1016/j.cell.2023.08.040. (2023).

[3] Sun N, et al. (https://pubmed.ncbi.nlm.nih.gov/37774678/) Human microglial state dynamics in Alzheimer’s disease progression. Cell. DOIi: 10.1016/j.cell.2023.08.037. (2023).

[4] Dileep V, et al. (https://pubmed.ncbi.nlm.nih.gov/37774679/) Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration. Cell. 2023 DOI: 10.1016/j.cell.2023.08.038. (2023).

NIH Support: National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute of General Medical Sciences

(https://directorsblog.nih.gov/2023/10/03/pain-circuit-discovery-in-the-brain-suggests-promising-alternative-to-opioid-painkillers/) Pain Circuit Discovery in the Brain Suggests Promising Alternative to Opioid Painkillers
Oct 3rd 2023, 09:00

A pain signal (red) is sent to a neuron in the brain. Researchers have identified a novel anti-pain pathway (blue) that works differently from opioids. Medicines activating this pathway could deliver pain relief long-term with limited risk for withdrawal symptoms or addiction. Credit Donny Bliss/NIH

Chronic pain is an often-debilitating health condition and serious public health concern, affecting more than 50 million Americans.1 The opioid and overdose crisis, which stems from inadequate pain treatment, continues to have a devastating impact on families and communities across the country. To combat both challenges, we urgently need new ways to treat acute and chronic pain effectively without the many downsides of opioids.

While there are already multiple classes of non-opioid pain medications and other approaches to manage pain, unfortunately none have proved as effective as opioids when it comes to pain relief. So, I’m encouraged to see that an NIH-funded team now has preclinical evidence of a promising alternative target for pain-relieving medicines in the brain.2

Rather than activating opioid receptors, the new approach targets receptors for a nerve messenger known as acetylcholine in a portion of the brain involved in pain control. Based on findings from animal models, it appears that treatments targeting acetylcholine could offer pain relief even in people who have reduced responsiveness to opioids. Their findings suggest that the treatment approach has the potential to remain effective in combatting pain long-term and with limited risk for withdrawal symptoms or addiction.

The researchers, led by Daniel McGehee, University of Chicago, focused their attention on non-opioid pathways in the ventrolateral periaqueductal gray (vlPAG), a brain area involved in pain control. They had previously shown that activating acetylcholine receptors, which are part of the vlPAG’s underlying circuitry, could relieve pain.3 However, they found that when the body is experiencing pain, it unexpectedly suppresses acetylcholine rather than releasing more.  

To understand how and why this is happening, McGehee and Shivang Sullere, now a postdoctoral fellow at Harvard Medical School, conducted studies in mice to understand how acetylcholine is released under various pain states. They found that mice treated with a drug that stimulates an acetylcholine receptor known as alpha-7 (⍺7) initially led to more activity in the nervous system. But this activity quickly gave way to a prolonged inactive or quiet state that delivered pain relief. Interestingly, this unexpected inhibitory effect lasted for several hours.

Additional studies in mice that had developed a tolerance to opioids showed the same long-lasting pain relief. This encouraging finding was expected since opioids use a pathway separate from acetylcholine. In more good news, the animals didn’t show any signs of dependence or addiction either. For instance, in the absence of pain, they didn’t prefer spending time in environments where they’d receive the ⍺7-targeted drug.  

Imaging studies measuring brain activity revealed greater activity in cells expressing ⍺7 with higher levels of pain. When that activity was blocked, pain levels dropped. The finding suggests to the researchers it may be possible to monitor pain levels through brain imaging. It’s also possible the acetylcholine circuitry in the brain may play a role in the process whereby acute or temporary pain becomes chronic.

Finding treatments to modify acetylcholine levels or target acetylcholine receptors may therefore offer a means to treat pain and prevent it from becoming chronic. Encouragingly, drugs acting on these receptors already have been tested for use in people for treating other health conditions. It will now be important to learn whether these existing therapeutics or others like them may act as highly effective, non-addictive painkillers, with important implications for alleviating chronic pain.

References:

[1] (https://heal.nih.gov/about/research-plan) NIH HEAL Initiative Research Plan. NIH HEAL Initiative.

[2] Sullere S et al. (https://pubmed.ncbi.nlm.nih.gov/37734381/) A cholinergic circuit that relieves pain despite opioid tolerance. Neuron. DOI: 10.1016/j.neuron.2023.08.017 (2023).

[3] Umana IC et al. (https://pubmed.ncbi.nlm.nih.gov/28817416/) Nicotinic modulation of descending pain control circuitry. Pain. PMID: 28817416; PMCID: PMC5873975 (2017).

Links:

(https://heal.nih.gov/) The Helping to End Addiction Long-term® (HEAL) Initiative (NIH)

(https://www.ninds.nih.gov/health-information/disorders/pain) Pain (National Institute of Neurological Disorders and Stroke/NIH)

(https://nida.nih.gov/research-topics/opioids) Opioids (National Institute on Drug Abuse/NIH)

(https://integrativephysiology.uchicago.edu/faculty/name/daniel-mcgehee/) Daniel McGehee (University of Chicago, Illinois)

NIH Support: National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse

(https://directorsblog.nih.gov/2023/09/28/words-matter-actions-have-impact-updating-the-nih-mission-statement/) Words Matter, Actions Have Impact: Updating the NIH Mission Statement
Sep 28th 2023, 09:00

Credit: Donny Bliss, NIH

I’ve previously written and spoken about how diverse perspectives are essential to innovation and scientific advancement.1 Scientists and experts with different backgrounds and lived experiences can offer diverse and creative solutions to solve complex problems. We’re taking steps to create a culture within the biomedical and behavioral research enterprise of inclusion, equity, and respect for every member of society. We are also working to strengthen our efforts to include populations in research that have not been historically included or equitably treated.

As part of our effort to ensure that all people are included in NIH research, we’re updating our (https://www.nih.gov/about-nih/what-we-do/nih-almanac/about-nih#:~:text=NIH%20is%20the%20steward%20of,and%20reduce%20illness%20and%20disability.) mission statement to reflect better the spirit of the agency’s work to optimize health for all people. The proposed, new statement is as follows:

“To seek fundamental knowledge about the nature and behavior of living systems and to apply that knowledge to optimize health and prevent or reduce illness for all people.”

Recently, we asked a team of (https://acd.od.nih.gov/working-groups/disabilitiessubgroup.html) subject matter experts to form a subgroup of the Advisory Committee to the Director’s Working Group on Diversity to advise NIH on how we can support the inclusion of people with disabilities in the scientific workforce and in the research enterprise. One of the subgroup’s (https://acd.od.nih.gov/documents/presentations/12092022_WGD_Disabilities_Subgroup_Report.pdf) recommendations was to update the current NIH mission statement to remove “reducing disability.” The subgroup explained that this language could be interpreted as perpetuating ableist beliefs that people with disabilities are flawed and need to be “fixed.”

Disability is often viewed solely as a medical problem requiring a cure or correction. However, this view can be stigmatizing as it focuses only on a perceived flaw in the individual. It does not account for how people identify and view themselves. It also does not account for the ways that society can be unaccommodating for people with disabilities.2,3 It’s important that we recognize the varied, nuanced and complex lived experiences among people with disabilities, many of whom may also face additional barriers as members of racial, ethnic, sexual and gender minority groups, people with lower incomes, and people who live in rural communities that are medically underserved.

Some of you may recall that we (https://www.nei.nih.gov/about/news-and-events/news/nih-mission-statement-amended) updated our mission statement in 2013 to remove phrasing that implied disability was a burden, since many people do not find their disabilities to be burdensome. As we re-examine our mission statement again in 2023, I’m reminded that strengthening diversity, equity, inclusion and accessibility (DEIA) is an ongoing process requiring our sustained engagement.

The input we’ve received has made it clear that words matter—language can perpetuate prejudices and implicit attitudes, which in turn can affect people’s behavior. We also acknowledge that it is time for the agency to review and consider how the words of our mission statement may affect the direction of our science.

In response, (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-23-163.html#:~:text=NIH's%20current%20mission%20statement%20is,and%20reduce%20illness%20and%20disability.%E2%80%9D) we are seeking the public’s input on the proposed, revised statement to ensure that it reflects the NIH mission as accurately as possible. The NIH mission should be inclusive of those who conduct research, those who participate in research, and those we serve—the American public. Anyone interested in providing feedback can send it to this (https://rfi.grants.nih.gov/?s=64caaa8bb1112e46ad0a1d52) submission website through Nov. 24, 2023.

We are grateful for the subgroup’s work and appreciate their time examining this issue in depth. I also want to recognize the helpful feedback that we’ve received from the disability community within NIH through the years, including recent listening sessions that helped guide the development of NIH’s (https://www.nih.gov/about-nih/nih-wide-strategic-plan-diversity-equity-inclusion-accessibility-deia) DEIA Strategic Plan.

Going beyond the scientific workforce, both the Strategic Plan and the subgroup’s report recognize the importance of research on health disparities. People with disabilities often experience health conditions leading to poorer health and face discrimination, inequality and structural barriers that inhibit access to health care, resulting in poorer health outcomes. NIH recently (https://www.nih.gov/news-events/news-releases/nih-designates-people-disabilities-population-health-disparities) designated people with disabilities as a population with health disparities to encourage research specific to the health issues and unmet health needs of the disability community. NIH also issued a (https://grants.nih.gov/grants/guide/pa-files/PAR-23-309.html) funding opportunity calling for research applications that address the intersecting impact of disability, race, ethnicity, and socioeconomic status on healthcare access and health outcomes.

The subgroup provided additional recommendations that we’re in the process of reviewing. We know one of our key challenges is data gathering that would give us a better snapshot of the workforce and the research we support. According to the CDC, (https://www.cdc.gov/ncbddd/disabilityandhealth/disability.html) 1 in 4 adults in the United States have a disability. However, in 2022 only (https://nexus.od.nih.gov/all/2022/12/13/data-on-researchers-self-reported-disability-status/) 1.3% of principal investigators on NIH research grant applications and awards self-reported a disability. In 2022, (https://www.edi.nih.gov/data/demographics) 8.6% of the NIH workforce reported having a disability; however, I recognize that this is likely not reflective of the true percentage. We know that some people do not want to self-disclose for numerous reasons, including the fear of discrimination.

We hope that, in part, changing the mission statement would be a step in the right direction of changing the culture at NIH and the larger biomedical and behavioral research enterprise. I know that our efforts have sometimes fallen short, but we will continually work to foster a culture of inclusive excellence where people with disabilities and all people feel like they truly belong and are embraced as an asset to the NIH mission.

References:

[1] MA Bernard et al. (https://www.nature.com/articles/s41591-021-01532-1#citeas) The US National Institutes of Health approach to inclusive excellence. Nature Medicine DOI:10.1038/s41591-021-01532-1 (2021)

[2] DS Dunn & EE Andrews. (https://pubmed.ncbi.nlm.nih.gov/25642702/) Person-first and identity-first language: Developing psychologists’ cultural competence using disability language The American Psychologist DOI: 10.1037/a0038636 (2015)

[3] International Classification of Functioning, Disability and Health (2002) Towards a Common Language for Functioning, Disability and Health. World Health Organization (https://cdn.who.int/media/docs/default-source/classification/icf/icfbeginnersguide.pdf) https://cdn.who.int/media/docs/default-source/classification/icf/icfbeginnersguide.pdf

Links:

(https://acd.od.nih.gov/working-groups/disabilitiessubgroup.html) ACD Working Group on Diversity, Subgroup on Individuals with Disabilities, NIH

(https://acd.od.nih.gov/documents/presentations/12092022_WGD_Disabilities_Subgroup_Report.pdf) Advisory Committee to the Director Working Group on Diversity Subgroup on Individuals with Disabilities: Report, NIH

(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-23-163.html) Request for Information: Inviting Comments and Suggestions on Updating the NIH Mission Statement, NIH

(https://www.nih.gov/news-events/news-releases/nih-designates-people-disabilities-population-health-disparities) NIH designates people with disabilities as a population with health disparities, Sept. 26, 2023, NIH News Releases

(https://www.nih.gov/about-nih/nih-wide-strategic-plan-diversity-equity-inclusion-accessibility-deia) NIH-Wide Strategic Plan for Diversity, Equity, Inclusion, and Accessibility (DEIA), NIH

(https://www.cdc.gov/ncbddd/disabilityandhealth/disability.html) Disability and Health Overview, CDC

(https://nexus.od.nih.gov/all/2022/12/13/data-on-researchers-self-reported-disability-status/) Data on Researchers’ Self-Reported Disability Status, NIH Office Of Extramural Research

(https://www.edi.nih.gov/data/demographics) Total NIH Workforce Demographics for Fiscal Year 2022 Fourth Quarter, NIH Office of Equity, Diversity, and Inclusion

(https://directorsblog.nih.gov/2023/09/26/revolutionizing-technology-to-treat-genetic-diseases-the-nih-targeted-challenge/) Revolutionizing Technology to Treat Genetic Diseases: The NIH TARGETED Challenge
Sep 26th 2023, 09:00

Recent scientific advances in the field of genome editing, which enables precise modifications to DNA, have greatly increased the potential to treat genetic diseases. Despite revolutionary progress in this area, treatment options remain limited. Several scientific challenges must be addressed before gene editing can be widely used in the clinic. For example, gene editing tools may cut in unintended areas in addition to the target site, and more research is necessary to understand how these errors affect patients.

Another key challenge is that many organs remain difficult to reach with gene therapies because we do not have adequate ways to deliver gene editing tools to all cells. While efficient delivery technologies exist for some targets, like liver cells, novel and specialized delivery methods designed for specific cell types and locations in the body are needed to ensure genome editing tools can reach sufficient numbers and types of somatic cells to modify DNA safely and effectively. Somatic cell gene therapies target non-reproductive cells, so the changes only affect the person who receives the gene therapy and are not passed down generation to generation.

To address these challenges, (https://commonfund.nih.gov/news/SCGE-TARGETED-Challenge-Launch) NIH launched the TARGETED (Targeted Genome Editor Delivery) Challenge, a multi-phase competition funded through the (https://commonfund.nih.gov/) NIH Common Fund as part of the (https://commonfund.nih.gov/editing) NIH Somatic Cell Genome Editing (SCGE) Program. SCGE was funded in 2018 to improve the efficacy and specificity of genome editing to help reduce the burden of common and rare diseases caused by genetic changes.

As part of the TARGETED Challenge, research teams will develop technologies for delivering genome editors to somatic cells. NIH will award up to $6 million in prize money across the challenge.

The Challenge is focused on finding delivery systems that can be programmed with biological or chemical tags that correspond to specific target cells and tissues. These tags would direct the delivery systems and the genome editing therapies to the target cells or tissues—like mail being delivered to different zip codes. Such programmable delivery systems would improve gene editing efficacy by targeting diseases at their source and would enhance safety by reducing undesired impacts on other tissues or cells. Ultimately, the development of safe and effective programmable delivery technologies for genome editors that are applicable to multiple diseases would help advance the application of gene editing therapies into the clinic.

The Challenge also is interested in gene editing delivery technologies that can cross the blood-brain barrier (BBB). The BBB protects the brain by blocking harmful substances from entering the fluid of the central nervous system. Unfortunately, it also blocks the uptake of many therapeutics, hindering treatments for brain diseases. While viruses are one of the few approaches that can be used as delivery systems to cross the BBB, they are expensive and difficult to make. Therefore, there is a pressing need for effective non-viral technologies to deliver genome editing machinery across the BBB to a substantial proportion of clinically relevant brain cell types. Such technologies could have broad implications for the treatment of many neurogenetic diseases.

Solutions to both target areas would not only provide proof-of-concept for the delivery of genome editing therapeutics, but they could be adapted to deliver other types of therapies to treat common and rare diseases in general.

The first phase of the Challenge began on May 15, 2023 and will run until October 5, 2023. More information about the Challenge is available on the (https://www.freelancer.com/nih/targeted-challenge) TARGETED Genome Editor Delivery Challenge website.

Links:

“(https://commonfund.nih.gov/news/SCGE-TARGETED-Challenge-Launch) National Institutes of Health launch TARGETED Challenge,” NIH Common Fund, May 15, 2023

(https://www.freelancer.com/nih/targeted-challenge) TARGETED Genome Editor Delivery Challenge (NIH Common Fund)

(https://commonfund.nih.gov/editing) Somatic Cell Genome Editing Program (NIH Common Fund)

NIH Support: The SCGE program is led by the NIH Common Fund, the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS). The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the National Heart, Lung, and Blood Institute (NHLBI) are also contributors to this Challenge.

(https://directorsblog.nih.gov/2023/09/21/researchamericas-national-health-research-forum/) Research!America’s National Health Research Forum
Sep 21st 2023, 11:51

(https://directorsblog.nih.gov/wp-content/uploads/2023/09/ResearchAmerica-9.20.23-3.jpg) On Sept. 20, 2023, I attended Research!America’s National Health Research Forum held at George Washington University in Washington, D.C. Here I am pictured with Mary Woolley (right), President and CEO of Research!America. We had a great discussion on a number of topics, including NIH’s RECOVER initiative to address long COVID, plans to update the NIH mission statement, how to communicate science and how we can prepare the next generation of researchers for the challenges ahead. 

(https://directorsblog.nih.gov/2023/09/19/rice-sized-device-tests-brain-tumors-drug-responses-during-surgery/) Rice-Sized Device Tests Brain Tumor’s Drug Responses During Surgery
Sep 19th 2023, 09:00

A device implanted into a tumor during surgery delivers tiny doses of up to 20 drugs to determine each treatment’s effects. Credit: Donny Bliss, NIH

Scientists have made remarkable progress in understanding the underlying changes that make cancer grow and have applied this knowledge to develop and guide targeted treatment approaches to vastly improve outcomes for people with many cancer types. And yet treatment progress for people with brain tumors known as gliomas—including the most aggressive glioblastomas—has remained slow. One reason is that doctors lack tests that reliably predict which among many therapeutic options will work best for a given tumor.

Now an NIH-funded team has developed a miniature device with the potential to change this for the approximately 25,000 people diagnosed with brain cancers in the U.S. each year [1]. When implanted into cancerous brain tissue during surgery, the rice-sized drug-releasing device can simultaneously conduct experiments to measure a tumor’s response to more than a dozen drugs or drug combinations. What’s more, a small clinical trial reported in Science Translational Medicine offers the first evidence in people with gliomas that these devices can safely offer unprecedented insight into tumor-specific drug responses [2].

These latest findings come from a Brigham and Women’s Hospital, Boston, team led by Pierpaolo Peruzzi and Oliver Jonas. They recognized that drug-screening studies conducted in cells or tissue samples in the lab too often failed to match what happens in people with gliomas undergoing cancer treatment. Wide variation within individual brain tumors also makes it hard to predict a tumor’s likely response to various treatment options.  

It led them to an intriguing idea: Why not test various therapeutic options in each patient’s tumor? To do it, they developed a device, about six millimeters long, that can be inserted into a brain tumor during surgery to deliver tiny doses of up to 20 drugs. Doctors can then remove and examine the drug-exposed cancerous tissue in the laboratory to determine each treatment’s effects. The data can then be used to guide subsequent treatment decisions, according to the researchers.

In the current study, the researchers tested their device on six study volunteers undergoing brain surgery to remove a glioma tumor. For each volunteer, the device was implanted into the tumor and remained in place for about two to three hours while surgeons worked to remove most of the tumor. Next, the device was taken out along with the last piece of a tumor at the end of the surgery for further study of drug responses.

Importantly, none of the study participants experienced any adverse effects from the device. Using the devices, the researchers collected valuable data, including how a tumor’s response changed with varying drug concentrations or how each treatment led to molecular changes in the cancerous cells.

More research is needed to better understand how use of such a device might change treatment and patient outcomes in the longer term. The researchers note that it would take more than a couple of hours to determine how treatments produce less immediate changes, such as immune responses. As such, they’re now conducting a follow-up trial to test a possible two-stage procedure, in which their device is inserted first using minimally invasive surgery 72 hours prior to a planned surgery, allowing longer exposure of tumor tissue to drugs prior to a tumor’s surgical removal.

Many questions remain as they continue to optimize this approach. However, it’s clear that such a device gives new meaning to personalized cancer treatment, with great potential to improve outcomes for people living with hard-to-treat gliomas.

References:

[1] National Cancer Institute Surveillance, Epidemiology, and End Results Program. (https://seer.cancer.gov/statfacts/html/brain.html) Cancer Stat Facts: Brain and Other Nervous System Cancer.

[2] Peruzzi P et al. (https://pubmed.ncbi.nlm.nih.gov/37672566/) Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas. Science Translational Medicine DOI: 10.1126/scitranslmed.adi0069 (2023).

Links:

(https://www.cancer.gov/types/brain) Brain Tumors – Patient Version (National Cancer Institute/NIH)

(https://physiciandirectory.brighamandwomens.org/details/12788/pier_paolo-peruzzi-neurosurgery-boston) Pierpaolo Peruzzi (Brigham and Women’s Hospital, Boston, MA)

(https://jonaslab.bwh.harvard.edu) Jonas Lab (Brigham and Women’s Hospital, Boston, MA)

NIH Support: National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Institute of Neurological Disorders and Stroke

(https://directorsblog.nih.gov/2023/09/12/new-approach-to-liquid-biopsy-relies-on-repetitive-rna-in-the-bloodstream/) New Approach to ‘Liquid Biopsy’ Relies on Repetitive RNA in the Bloodstream
Sep 12th 2023, 09:00

(https://directorsblog.nih.gov/wp-content/uploads/2023/09/RNA-Blood-post.jpg) Researchers have identified segments of noncoding RNA circulating in the blood that are early signs of cancer. Credit: Modified from Adobe Stock/ Andrey Popov; Donny Bliss, NIH

It’s always best to diagnose cancer at an early stage when treatment is most likely to succeed. Unfortunately, far too many cancers are still detected only after cancer cells have escaped from a primary tumor and spread to distant parts of the body. This explains why there’s been so much effort in recent years to develop (https://prevention.cancer.gov/major-programs/liquid-biopsy-consortium) liquid biopsies, which are tests that can pick up on circulating cancer cells or molecular signs of cancer in blood or other bodily fluids and reliably trace them back to the organ in which a potentially life-threatening tumor is growing.

(https://directorsblog.nih.gov/2018/01/30/new-liquid-biopsy-shows-early-promise-in-detecting-cancer/) Earlier methods to develop liquid biopsies for detecting cancers often have relied on the presence of cancer-related proteins and/or DNA in the bloodstream. Now, an NIH-supported research team has encouraging evidence to suggest that this general approach to detecting cancers—including aggressive pancreatic cancers—may work even better by taking advantage of signals from a lesser-known form of genetic material called noncoding RNA.

The findings reported in Nature Biomedical Engineering suggest that the new liquid biopsy approach may aid in the diagnosis of many forms of cancer [1]. The studies show that the sensitivity of the tests varies—a highly sensitive test is one that rarely misses cases of disease. However, they already have evidence that millions of circulating RNA molecules may hold promise for detecting cancers of the liver, esophagus, colon, stomach, and lung.

How does it work? The human genome contains about 3 billion paired DNA letters. Most of those letters are transcribed, or copied, into single-stranded RNA molecules. While RNA is best known for encoding proteins that do the work of the cell, most RNA never gets translated into proteins at all. This noncoding RNA includes repetitive RNA that can be transcribed from millions of repeat elements—patterns of the same few DNA letters occurring multiple times in the genome.

Common approaches to studying RNA don’t analyze repetitive RNA, so its usefulness as a diagnostic tool has been unclear—until recently. Last year, the lab of Daniel Kim at the University of California, Santa Cruz reported [2] that a key genetic mutation that occurs early on in some cancers causes repetitive RNA molecules to be secreted in large quantities from cancer cells, even at the earliest stages of cancer. Non-cancerous cells, by comparison, release much less repetitive RNA.

The findings suggested that liquid biopsy tests that look for this repetitive, noncoding RNA might offer a powerful new way to detect cancers sooner, according to the authors. But first they needed a method capable of measuring it. Due to its oftentimes uncertain functions, the researchers have referred to repetitive, noncoding RNA as “dark matter.”

Using a liquid biopsy platform they developed called COMPLETE-seq, Kim’s team trained computers to detect cancers by looking for patterns in RNA data. The platform enables sequencing and analysis of all protein coding and noncoding RNAs—including any RNA from more than 5 million repeat elements—present in a blood sample. They found that their classifiers worked better when repetitive RNAs were included. The findings lend support to the idea that repetitive, noncoding RNA in the bloodstream is a rich source of information for detecting cancers, which has previously been overlooked.

In a study comparing blood samples from healthy people to those with pancreatic cancer, the COMPLETE-seq technology showed that nearly all people in the study with pancreatic cancer had more repetitive, noncoding RNA in their blood samples compared to healthy people, according to the researchers. They used the COMPLETE-seq test on blood samples from people with other types of cancer as well. For example, their test accurately detected 91% of colorectal cancer samples and 93% of lung cancer samples.

They now plan to look at many more cancer types with samples from additional patients representing a broad range of cancer stages. The goal is to develop a single RNA liquid biopsy test that could detect multiple forms of cancer with a high degree of accuracy and specificity. They note that such a test might also be used to guide treatment decisions and more readily detect a cancer’s recurrence. The hope is that one day a comprehensive liquid biopsy test including coding and noncoding RNA will catch many more cancers sooner, when treatment can be most successful.

References:

[1] RE Reggiardo et al. (https://pubmed.ncbi.nlm.nih.gov/37652985/) Profiling of repetitive RNA sequences in the blood plasma of patients with cancer. Nature Biomedical Engineering DOI: 10.1038/s41551-023-01081-7 (2023).

[2] RE Reggiardo et al. (https://pubmed.ncbi.nlm.nih.gov/35858545/) Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes. Cell Reports DOI: 10.1016/j.celrep.2022.111104 (2022).

Links:

(https://dkim.sites.ucsc.edu) Daniel Kim Lab (UC Santa Cruz)

(https://www.cancer.gov/about-cancer/screening/patient-screening-overview-pdq) Cancer Screening Overview (National Cancer Institute/NIH)

(https://prevention.cancer.gov/research-groups/early-detection) Early Detection (National Cancer Institute/NIH)

NIH Support: National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases

(https://directorsblog.nih.gov/2023/08/30/nih-welcomes-tribal-leaders-for-annual-tribal-advisory-committee-meeting/) NIH Welcomes Tribal Leaders for Annual Tribal Advisory Committee Meeting
Aug 30th 2023, 13:15

Dr. Karina Walters, Ph.D., director of NIH’s Tribal Health Research Office and I were pleased to welcome Tribal leaders and representatives to the NIH campus on Aug. 16 and 17. These Tribal officials provide input and recommendations on NIH research policies, programs, priorities and other activities that affect American Indian/Alaska Native populations. In addition to many productive discussions, the Tribal officials toured the NIH Clinical Center where they spoke to researchers from the National Heart, Lung, and Blood Institute. Left to right: Alicia C. Mousseau, Ph.D. (Oglala Sioux); Stephen Kutz, M.P.H. (Cowlitz Indian); me; Karina Walters, Ph.D. (Choctaw Nation) Director, Tribal Health Research Office; Debra Danforth, R.N., B.S.N. (Oneida Nation); Herminia Frias, M.P.H. (Pascua Yaqui Tribe), TAC Chairperson; Brittany Jock, Ph.D. (Mohawk); Donna Galbreath, M.D. (Ahtna Athabascan). Credit: Chiachi Chang, NIH

(https://directorsblog.nih.gov/2023/08/22/how-to-feed-a-macrophage/) How to Feed a Macrophage
Aug 22nd 2023, 09:00

Credit: Annalise Bond, Morrissey Lab, University of California, Santa Barbara

For Annalise Bond, a graduate student in the lab of Meghan Morrissey, University of California, Santa Barbara (UCSB), macrophages are “the professional eaters of our immune system.” Every minute of every day, macrophages somewhere in the body are gorging themselves to remove the cellular debris that builds up in our tissues and organs.

In this image, Bond caught several macrophages (green) doing what they do best: shoveling it in—in this case, during a lab experiment. The macrophages are consuming silica beads (purple) prepared with biochemicals that whet their appetites. Each bead measures about five microns in diameter. That’s roughly the size of a bacterium or a spent red blood cell—debris that a macrophage routinely consumes.

When Bond snapped this image, she noticed a pattern that reminded her of a childhood tabletop game called Hungry Hungry Hippos. Kids press a lever attached to the mouth of a plastic hippo, its lower jaw flaps open, and the challenge is to fill the mouth with as many marbles as possible . . . just like the macrophages eating beads.

Bond adjusted the colors in the photo to make them pop. She then entered it into UCSB’s 2023 Art of Science contest with the caption of Hungry Hungry Macrophages, winning high marks for drawing the association.

Though the caption was written in fun, Bond studies in earnest a fascinating biological question: How do macrophages know what to eat in the body and what to leave untouched?

In her studies, Bond coats the silica beads shown above with a lipid bilayer to mimic a cell membrane. To that coating, she adds various small molecules and proteins as “eat-me” signals often found on the surface of dying cells. Some of the signals are well characterized; but many aren’t, meaning there’s still a lot to learn about what makes a macrophage “particularly hungry” and what makes a particular target cell “extra tasty.”

Capturing fluorescent images of macrophages under the microscope, Bond counts up how many beads are eaten. Beads bearing no signal to stimulate their appetite might get eaten occasionally. But when an especially enticing signal is added, macrophages will gorge themselves until they can’t eat anymore.

In the experiment pictured above, the beads contain the antibody immunoglobulin G (IgG), which tags foreign pathogens for macrophage removal. Interestingly, IgG antibody responses also play an important role in cancer immunotherapies, in which the immune system is unleashed to fight cancer.

Among its many areas of study, the NIH-supported Morrissey lab’s wants to understand better how macrophages interact with cancer cells. They want to learn how to make cancer cells even tastier to macrophages and program their elimination from the body. Sorting out the signals will be challenging, but we know that macrophages will take a bite at the right ones. They are, after all, professional eaters.

Links:

(https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/cancer-immunotherapy) Cancer Immunotherapy (NIH)

(https://morrisseylab.mcdb.ucsb.edu/people/annalise-bond) Annalise Bond (University of California, Santa Barbara)

(https://morrisseylab.mcdb.ucsb.edu/) Morrissey Lab (University of California, Santa Barbara)

(https://art-csep.cnsi.ucsb.edu) Art of Science (University of California, Santa Barbara)

NIH Support: National Institute of General Medical Sciences

(https://directorsblog.nih.gov/2023/08/15/science-serendipity-and-art/) Science, Serendipity, and Art
Aug 15th 2023, 09:00

Credit: Bryan Bogin and Matthew Steinsaltz, Zachary Levine Lab, Yale University School of Medicine, New Haven, CT

Fractals are complex geometric patterns repeated at progressively smaller scales. You’ll find them throughout nature. That includes in the 3D structures and shapes of tissues throughout our bodies, from the bones in our skulls down to the blood vessels in our feet. But the fractal pattern above isn’t from a precisely patterned human tissue. It comes from some unexpected biochemistry that formed the stunning pattern on its own.

In fact, the exact source for this fractal pattern reminiscent of peacock feathers isn’t known. It turned up out of the blue (and green) in a sample that had been sitting around on the shelf for some time. The original image appeared in black and white, but the colors added post-collection help to highlight the fractal pattern of a sample including an essential hormone produced in the pancreas. The hormone is called islet amyloid polypeptide (IAPP).

Also known as amylin, IAPP plays many important roles in our bodies, including the feeling of fullness after a meal. But the amino acid chains that make up IAPP also are prone to forming abnormal clumps of misfolded polypeptides (a long name for proteins) known as amyloids. Much like the amyloid plaques in the brains of people with Alzheimer’s disease, misfolded IAPP amyloids in people with type 2 diabetes also can damage insulin-producing beta cells in the pancreas and make controlling their blood sugar levels even more difficult.

This unusual image comes from graduate students Bryan Bogin and Matthew Steinsaltz. They study the biophysics and biochemistry of protein folding and misfolding in the lab of Zachary Levine, Yale School of Medicine, New Haven, CT. The Levine lab recently moved to the Altos Labs San Diego Institute. However, Bogin and Steinsaltz continue to conduct their studies at Yale.

The two conduct in-solution experiments and molecular simulations to elucidate the precise conditions and triggers that can lead otherwise normal polypeptide chains to fold up incorrectly and wreak havoc as they do in diabetes and other diseases. When Steinsaltz was learning how to use transmission electron microscopy (TEM), a technique in which an electron beam captures images including detailed molecular-level structures, Bogin handed over an assortment of IAPP samples in different solution conditions from some of his past experiments for a look.

In those microscopy images, they expected to see long, linear fibrils consisting of IAPP polypeptides. While that’s indeed what they saw in most of the samples, this one was the exception. It was such a remarkable image that they submitted it in the Biophysical Society’s (https://www.biophysics.org/awards-funding/image-contest#/) 2022 Art of Science Image Contest, where it took the top prize.

Bogin and Steinsaltz say they still can’t explain the source or meaning behind these unusual fractal patterns. But they do continue to conduct experiments to understand how various polypeptides implicated in health and disease misfold to form destructive aggregates. This striking image may not hold the answers they seek, but it is an inspiring reminder that the path to making groundbreaking biomedical discoveries will have many beautiful surprises along the way.

Links:

(https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/type-2-diabetes) Type 2 Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

(https://medicine.yale.edu/profile/zachary-levine/) Zachary Levine Lab (Yale School of Medicine, New Haven, CT)

(https://www.biophysics.org/awards-funding/image-contest#/) Art of Science Image Contest (Biophysical Society, Rockville, MD)

NIH Support: National Institute on Aging

(https://directorsblog.nih.gov/2023/08/10/nih-welcomes-visitors-from-ostp/) NIH Welcomes Visitors from OSTP
Aug 10th 2023, 14:24

It was my pleasure to welcome Arati Prabhakar (2nd from right) during her visit to NIH on August 3. Dr. Prabhakar is director of the White House Office of Science and Technology Policy (OSTP) and assistant to the President for Science and Technology. Joining her on the visit was Travis Hyams, senior policy advisor for Health Outcomes Division, OSTP (to my left). While on campus, Dr. Prabhakar met with me and NIH Institute and Center directors and toured two labs in the NIH Clinical Center. In this photo, John Tisdale, senior investigator at the National Heart, Lung, and Blood Institute (far right) talks to Dr. Prabhakar about sickle cell research. Also pictured is Courtney Fitzhugh (far left), who leads NHLBI’s Laboratory of Early Sickle Mortality Prevention. Credit: Chiachi Chang, NIH


(https://directorsblog.nih.gov/2023/08/08/how-neurons-make-connections/) How Neurons Make Connections
Aug 8th 2023, 09:00

Credit: Emily Heckman, Doe Lab, University of Oregon, Eugene 

For many people, they are tiny pests. These fruit flies that sometimes hover over a bowl of peaches or a bunch of bananas. But for a dedicated community of researchers, fruit flies are an excellent model organism and source of information into how neurons self-organize during the insect’s early development and form a complex, fully functioning nervous system.

That’s the scientific story on display in this beautiful image of a larval fruit fly’s developing nervous system. Its subtext is: fundamental discoveries in the fruit fly, known in textbooks as Drosophila melanogaster, provide basic clues into the development and repair of the human nervous system. That’s because humans and fruit flies, though very distantly related through the millennia, still share many genes involved in their growth and development. In fact, 60 percent of the Drosophila genome is identical to ours.

Once hatched, as shown in this image, a larval fly uses neurons (magenta) to sense its environment. These include neurons that sense the way its body presses against the surrounding terrain, as needed to coordinate the movements of its segmented body parts and crawl in all directions.

This same set of neurons will generate painful sensations, such as the attack of a parasitic wasp. Paintbrush-like neurons in the fly’s developing head (magenta, left side) allow the insect to taste the sweetness of a peach or banana.

There is a second subtype of neurons, known as proprioceptors (green). These neurons will give the young fly its “sixth sense” understanding about where its body is positioned in space. The complete collection of developing neurons shown here are responsible for all the fly’s primary sensations. They also send these messages on to the insect’s central nervous system, which contains thousands of other neurons that are hidden from view.

Emily Heckman, now a postdoctoral researcher at the Michigan Neuroscience Institute, University of Michigan, Ann Arbor, captured this image during her graduate work in the lab of Chris Doe, University of Oregon, Eugene. For her keen eye, she received a trainee/early-career BioArt Award from the Federation of American Societies for Experimental Biology (FASEB), which each year (https://www.faseb.org/awards/bioart) celebrates the art of science.

The image is one of many from a much larger effort in the Doe lab that explores the way neurons that will partner find each other and link up to drive development. Heckman and Doe also wanted to know how neurons in the developing brain interconnect into integrated neural networks, or circuits, and respond when something goes wrong. To find out, they disrupted sensory neurons or forced them to take alternate paths and watched to see what would happen.

As published in the journal eLife [1], the system has an innate plasticity. Their findings show that developing sensory neurons instruct one another on how to meet up just right. If one suddenly takes an alternate route, its partner can still reach out and make the connection. Once an electrically active neural connection, or synapse, is made, the neural signals themselves slow or stop further growth. This kind of adaptation and crosstalk between neurons takes place only during a particular critical window during development.

Heckman says part of what she enjoys about the image is how it highlights that many sensory neurons develop simultaneously and in a coordinated process. What’s also great about visualizing these events in the fly embryo is that she and other researchers can track many individual neurons from the time they’re budding stem cells to when they become a fully functional and interconnected neural circuit.

So, the next time you see fruit flies hovering in the kitchen, just remember there’s more to their swarm than you think. Our lessons learned studying them will help point researchers toward new ways in people to restore or rebuild neural connections after devastating disruptions from injury or disease.

Reference:

(https://pubmed.ncbi.nlm.nih.gov/36448675/) Presynaptic contact and activity opposingly regulate postsynaptic dendrite outgrowth. Heckman EL, Doe CQ. Elife. 2022 Nov 30;11:e82093.

Links:

(https://nigms.nih.gov/education/fact-sheets/Pages/using-research-organisms.aspx) Research Organisms (National Institute of General Medical Sciences/NIH)

(https://www.doelab.org/) Doe Lab (University of Oregon, Eugene)

(https://medicine.umich.edu/dept/mni/emily-heckman-phd) Emily Heckman (University of Michigan, Ann Arbor)

(https://www.faseb.org/awards/bioart) BioArt Awards (Federation of American Societies for Experimental Biology, Rockville, MD)

NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development

(https://directorsblog.nih.gov/2023/08/01/3d-animation-captures-viral-infection-in-action/) 3D Animation Captures Viral Infection in Action
Aug 1st 2023, 09:00

With the summer holiday season now in full swing, the blog will also swing into its annual August series. For most of the month, I will share with you just a small sampling of the colorful videos and snapshots of life captured in a select few of the hundreds of NIH-supported research labs around the country.

To get us started, let’s turn to the study of viruses. Researchers now can generate vast amounts of data relatively quickly on a virus of interest. But data are often displayed as numbers or two-dimensional digital images on a computer screen. For most virologists, it’s extremely helpful to see a virus and its data streaming in three dimensions. To do so, they turn to a technological tool that we all know so well: animation.

This research animation features the (https://www.cdc.gov/chikungunya/index.html) chikungunya virus, a sometimes debilitating, mosquito-borne pathogen transmitted mainly in developing countries in Africa, Asia and the Americas. The animation illustrates large amounts of research data to show how the chikungunya virus infects our cells and uses its specialized machinery to release its genetic material into the cell and seed future infections. Let’s take a look. 

In the opening seconds, you see how receptor binding glycoproteins (light blue), which are proteins with a carbohydrate attached on the viral surface, dock with protein receptors (yellow) on a host cell. At five seconds, the virus is drawn inside the cell. The change in the color of the chikungunya particle shows that it’s coated in a (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/vesicle) vesicle, which helps the virus make its way unhindered through the cytoplasm. 

At 10 seconds, the virus then enters an endosome, ubiquitous bubble-like compartments that transport material from outside the cell into the cytosol, the fluid part of the cytoplasm. Once inside the endosome, the acidic environment makes other glycoproteins (red, blue, yellow) on the viral surface change shape and become more flexible and dynamic. These glycoproteins serve as machinery that enables them to reach out and grab onto the surrounding endosome membrane, which ultimately will be fused with the virus’s own membrane.

As more of those fusion glycoproteins grab on, fold back on themselves, and form into hairpin-like shapes, they pull the membranes together. The animation illustrates not only the changes in protein organization, but the resulting effects on the integrity of the membrane structures as this dynamic process proceeds. At 53 seconds, the viral protein shell, or capsid (green), which contains the virus’ genetic instructions, is released back out into the cell where it will ultimately go on to make more virus.

This remarkable animation comes from Margot Riggi and Janet Iwasa, experts in visualizing biology at the University of Utah’s Animation Lab, Salt Lake City. Their data source was researcher Kelly Lee, University of Washington, Seattle, who collaborated closely with Riggi and Iwasa on this project. The final product was considered so outstanding that it took the top prize for short videos in the 2022 BioArt Awards competition, sponsored by the Federation of American Societies for Experimental Biology (FASEB).

The Lee lab uses various research methods to understand the specific shape-shifting changes that chikungunya and other viruses perform as they invade and infect cells. One of the lab’s key visual tools is (https://directorsblog.nih.gov/2016/01/14/got-it-down-cold-cryo-electron-microscopy-named-method-of-the-year/) cryo-electron microscopy (Cryo-EM), specifically cryo-electron tomography (cryo-ET). Cryto-ET enables complex 3D structures, including the intermediate state of biological reactions, to be captured and imaged in remarkably fine detail. 

In a study in the journal Nature Communications [1] last year, Lee’s team used cryo-ET to reveal how the chikungunya virus invades and delivers its genetic cargo into human cells to initiate a new infection. While Lee’s cryo-ET data revealed stages of the virus entry process and fine structural details of changes to the virus as it enters a cell and starts an infection, it still represented a series of snapshots with missing steps in between. So, Lee’s lab teamed up with The Animation Lab to help beautifully fill in the gaps.

Visualizing chikungunya and similar viruses in action not only makes for informative animations, it helps researchers discover better potential targets to intervene in this process. This basic research continues to make progress, and so do ongoing efforts to develop a chikungunya vaccine [2] and specific treatments that would help give millions of people relief from the aches, pains, and rashes associated with this still-untreatable infection.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/35970990/) Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery. Mangala Prasad V, Blijleven JS, Smit JM, Lee KK. Nat Commun. 2022 Aug 15;13(1):4772. doi: 10.1038/s41467-022-32431-9. PMID: 35970990; PMCID: PMC9378758.

[2] (https://www.niaid.nih.gov/news-events/experimental-chikungunya-vaccine-safe-and-well-tolerated-early-trial) Experimental chikungunya vaccine is safe and well-tolerated in early trial, National Institute of Allergy and Infectious Diseases news release, April 27, 2020.

Links:

(https://www.cdc.gov/chikungunya/index.html) Chikungunya Virus (Centers for Disease Control and Prevention, Atlanta)

(https://www.who.int/news-room/events/detail/2022/03/31/default-calendar/global-arbovirus-initiative) Global Arbovirus Initiative (World Health Organization, Geneva, Switzerland)

(https://animationlab.utah.edu/) The Animation Lab (University of Utah, Salt Lake City)

Video: (https://www.ted.com/speakers/janet_iwasa) Janet Iwasa (TED Speaker)

(https://www.lee-lab-fusion.org/) Lee Lab (University of Washington, Seattle)

(https://www.faseb.org/awards/bioart) BioArt Awards (Federation of American Societies for Experimental Biology, Rockville, MD)

NIH Support: National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases

(https://directorsblog.nih.gov/2023/07/25/cryo-em-scores-again/) Cryo-EM Scores Again
Jul 25th 2023, 09:00

Caption: Researchers recently published the near-atomic structure of the neuronal pore CALHMI. Credit: Donny Bliss, NIH

Human neurons are (https://directorsblog.nih.gov/2021/08/03/the-amazing-brain-toward-a-wiring-diagram-of-connectivity/) l(https://directorsblog.nih.gov/2021/08/03/the-amazing-brain-toward-a-wiring-diagram-of-connectivity/) ong, spindly structures, but if you could zoom in on their surfaces at super-high resolution, you’d see surprisingly large pores. They act as gated channels that open and close for ions and other essential molecules of life to pass in and out the cell. This rapid exchange of ions and other molecules is how neurons communicate, and why we humans can sense, think, move, and respond to the world around us [1].

Because these gated channels are so essential to neurons, mapping their precise physical structures at high-resolution has profound implications for informing future studies on the brain and nervous system. Good for us in these high-tech times that structural biologists keep getting better at imaging these 3D pores.

In fact, as just published in the journal Nature Communications [2], a team of NIH-supported scientists imaged the molecular structure of a gated pore of major research interest. The pore is called calcium homeostasis modulator 1 (CALHM1). Pictured below, you can view its 3D structure at near atomic resolution [2]. Keep in mind, this relatively large neuronal pore still measures approximately 50,000 times smaller than the width of a hair.

Caption: Human CALHM1 channel. It has an eight-protein assembly pattern. Note the different colored arm-like structures above. White dot (center) is ruthenium red, a chemical that blocks off the channel. Credit: Furkawa lab/Cryo-EM Facility/Cold Spring Harbor Laboratory, NY

The structure comes from a research team led by Hiro Furukawa, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. He and his team relied on cryo-electron microscopy (cryo-EM) to produce the first highly precise 3D models of CALHM1.

(https://directorsblog.nih.gov/2016/01/14/got-it-down-cold-cryo-electron-microscopy-named-method-of-the-year/) Cryo-EM involves flash-freezing molecules in liquid ethane and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can reveal the structure of intricate macromolecular complexes in a matter of weeks.

Furukawa’s team had earlier studied CALHM1 from chickens with cryo-EM [3], and their latest work reveals that the human version is quite similar. Eight copies of the CALHM1 protein assemble to form the circular channel. Each of the protein subunits has a flexible arm that allows it to reach into the central opening, which the researchers now suspect allows the channels to open and close in a highly controlled manner. The researchers have likened the channels’ eight flexible arms to the arms of an octopus.

The researchers also found that fatty molecules called (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/phospholipid) phospholipids play a critical role in stabilizing and regulating the eight-part channel. They used simulations to demonstrate how pockets in the CALHM1 channel binds this phospholipid over cholesterol to shore up the structure and function properly. Interestingly, these phospholipid molecules are abundant in many healthy foods, such as eggs, lean meats, and seafood.

Researchers knew that an inorganic chemical called ruthenium red can block the function of the CALHM1 channel. They’ve now shown precisely how this works. The structural details indicate that ruthenium red physically lodges in and plugs up the channel.

These details also may be useful in future efforts to develop drugs designed to target and modify the function of these channels in helpful ways. For instance, on our tongues, the channel plays a role in our ability to perceive sweet, sour, or umami (savory) flavors. In our brains, studies show the abnormal function of CALHM1 may be implicated in the plaques that accumulate in the brains of people with Alzheimer’s disease.

There are far too many other normal and abnormal functions to mention here in this brief post. Suffice it to say, I’ll look forward to seeing what this enabling research yields in the years ahead.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/33865869/) On the molecular nature of large-pore channels. Syrjanen, J., Michalski, K., Kawate, T., and Furukawa, H. J Mol Biol. 2021 Aug 20;433(17):166994. DOI: 10.1016/j.jmb.2021.166994. Epub 2021 Apr 16. PMID: 33865869; PMCID: PMC8409005. 

[2] (https://pubmed.ncbi.nlm.nih.gov/37380652/) Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red. Syrjänen JL, Epstein M, Gómez R, Furukawa H. Nat Commun. 2023 Jun 28;14(1):3821. DOI: 10.1038/s41467-023-39388-3. PMID: 37380652; PMCID: PMC10307800.

[3] (https://pubmed.ncbi.nlm.nih.gov/31988524/) Structure and assembly of calcium homeostasis modulator proteins. Syrjanen JL, Michalski K, Chou TH, Grant T, Rao S, Simorowski N, Tucker SJ, Grigorieff N, Furukawa H. Nat Struct Mol Biol. 2020 Feb;27(2):150-159. DOI: 10.1038/s41594-019-0369-9. Epub 2020 Jan 27. PMID: 31988524; PMCID: PMC7015811.

Links:

(https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-life-and-death-neuron) Brain Basics: The Life and Death of a Neuron (National Institute of Neurological Disorders and Stroke/NIH)

(https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet) Alzheimer’s Disease (National Institute on Aging/NIH)

(https://furukawalab.labsites.cshl.edu) Furukawa Lab (Cold Spring Harbor Lab, Cold Spring Harbor, NY)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health

(https://directorsblog.nih.gov/2023/07/18/understanding-causes-of-devastating-neurodegenerative-condition-affecting-children/) Understanding Causes of Devastating Neurodegenerative Condition Affecting Children
Jul 18th 2023, 09:00

Researchers studied the lack of functional CLN3 protein, which underlies Batten disease. They found lack of the protein leads to a breakdown of the M6PR receptor (green) in the lysosomes and subsequent disruption of needed lysosomal enzymes and the formation of normal lysosomes. Credit: Donny Bliss, NIH

A common theme among parents and family members caring for a child with the rare (https://www.ninds.nih.gov/health-information/disorders/batten-disease) Batten disease is “love, hope, cure.” While inspiring levels of love and hope are found among these amazing families, a cure has been more elusive. One reason is rooted in the need for more basic research. Although researchers have identified an altered gene underlying Batten disease, they’ve had difficulty pinpointing where and how the gene’s abnormal protein product malfunctions, especially in cells within the nervous system.

Now, this investment in more basic research has paid off. In a paper just published in the journal Nature Communications, an international research team pinpointed where and how a key cellular process breaks down in the nervous system to cause Batten disease, sometimes referred to as CLN3 disease [1]. While there’s still a long way to go in learning exactly how to overcome the cellular malfunction, the findings mark an important step forward toward developing targeted treatments for Batten disease and progress in the quest for a cure.

The research also offers yet another excellent example of how studying rare diseases helps to advance our fundamental understanding of human biology. It shows that helping those touched by Batten disease can shed a brighter light on basic cellular processes that drive other diseases, rare and common.

Batten disease affects about 14,000 people worldwide [2]. For those with the juvenile form of this inherited disease of the nervous system, parents may first notice their seemingly healthy child has difficulty saying words, sudden problems with vision or movement, and changes in behavior. Tragically for parents, with no approved treatments to reverse these symptoms, the disease will worsen, leading to severe vision loss, frequent seizures, and impaired motor skills. The disease can be fatal as early as late childhood or the teenage years.

Batten disease also goes by the more technical name of juvenile (https://rarediseases.info.nih.gov/diseases/10739/neuronal-ceroid-lipofuscinosis) neuronal ceroid lipofuscinosis. Using this technical name, it represents one of the more than 70 medically recognized lysosomal storage disorders.

These disorders share a breakdown in the ability of membrane-bound cellular components, known as (https://www.genome.gov/genetics-glossary/Lysosome#:~:text=A%20lysosome%20is%20a%20membrane,or%20worn-out%20cell%20parts.) lysosomes, to degrade the molecular waste products of normal cell biology. As a result, all this undegraded material builds up and eventually kills affected cells. In people with Batten disease, the lost and damaged cells cause progressive dysfunction within the nervous system.

Researchers have known for a while that the most common cause of this breakdown in people with Batten disease is the inheritance of two defective copies of a gene called (https://www.ncbi.nlm.nih.gov/gene/1201) CLN3. As mentioned above, what’s been missing is a more detailed understanding of what exactly a working copy of the CLN3 gene does and how its loss leads to the changes seen in those with this condition.

Hoping to solve this puzzle was an NIH-supported basic research team led by Alessia Calcagni and Andrea Ballabio, Baylor College of Medicine and Texas Children’s Hospital, Houston, and Telethon Institute of Genetics and Medicine, Naples, Italy.

As described in their latest paper, the researchers first generated an antibody that allowed them to visualize where in cells the protein encoded by CLN3 is found. Their studies unexpectedly showed that this protein has a role outside, not inside, the cell’s estimated 50-to-1,000 lysosomes. Before reaching the lysosomes, the protein first moves through another cellular component called the (https://www.genome.gov/genetics-glossary/golgi-body) Golgi body, where many proteins are packaged.

They then identified all the other proteins that interact with the CLN3 protein in the Golgi body and elsewhere in the cell. Their data showed that CLN3 interacts with proteins known for transporting other proteins within the cell and forming new lysosomes.

That gave them a valuable clue: the CLN3 gene must be a player in these fundamentally important cellular processes of protein transport and lysosome formation. Among the proteins CLN3 interacts with in the Golgi body is a particular receptor called M6PR. The receptor known for its role in recognizing lysosomal enzymes and delivering them to the lysosomes, where they go to work inside these bubble-like structures degrading cellular waste products.

The researchers found that loss of CLN3 led this important M6PR receptor to be broken down within lysosomes. The breakdown, in turn, altered the normal shape of new lysosomes, and that limits their functionality. The researchers also showed that restoring CLN3 in cells that lacked this gene also restored the production of more functional lysosomes and lysosomal enzymes.

Overall, the findings point to a major role for CLN3 in the formation of lysosomes and their ability to function. Importantly, the findings also offer clues for understanding the mechanisms that underlie other forms of lysosomal storage disease, which collectively affect as many as one in every 40,000 people [3]. The work also may have broader implications for common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease.

Most of all, this paper demonstrates the power of basic research to define needed molecular targets. It shows how these fundamental studies are helping families affected by Batten disease and supporting their love, hope, and quest for a cure.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37400440/) Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation. Calcagni’ A, Staiano L, Zampelli N, Minopoli N, Herz NJ,  Cullen PJ, Parenti G, De Matteis MA, Grumati P, Ballabio A, et al. Nat Commun. 2023 Jul 3;14(1):3911. doi: 10.1038/s41467-023-39643-7. PMID: 37400440; PMCID: PMC10317969.

[2] (https://www.childrenshospital.org/conditions/batten-disease#:~:text=Some%20children%20die%20in%20early,out%20of%20every%20100%2C000%20children) Batten Disease. Boston Children’s Hospital.

[3] (https://my.clevelandclinic.org/health/diseases/23383-lysosomal-storage-diseases#:~:text=Lysosomal%20storage%20diseases%20or%20disorders,(enzyme%20activator%20or%20modifier) Lysosomal storage diseases. Cleveland Clinic fact sheet, June 27, 2022.

Links:

(https://www.ninds.nih.gov/health-information/disorders/batten-disease) Batten Disease (National Institute of Neurological Disorders and Stroke/NIH)

(https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/rare-diseases) Rare Diseases (NIH)

(https://www.bcm.edu/people-search/alessia-calcagni-19106) Alessia Calcagni (Baylor College of Medicine, Houston, TX)

(https://ballabio.tigem.it) Andrea Ballabio (Telethon Institute of Genetics and Medicine, Naples, Italy)

NIH Support: National Institute of Neurological Disorders and Stroke; National Cancer Institute; National Center for Advancing Translational Sciences

(https://directorsblog.nih.gov/2023/07/03/visit-the-new-nih-virtual-tour/) Visit the New NIH Virtual Tour
Jul 3rd 2023, 11:30

Happy Fourth of July! Before everyone heads out to celebrate the holiday with their family and friends, I want to share this brief video with you. It’s an introduction to the brand-new NIH Virtual Tour that’s now available on our website. When time permits, I encourage everyone to (https://www.nih.gov/virtual-tour/) take the full tour of our Bethesda, MD, main campus and explore this great institution of science, technological innovation, and, above all, hope.

Among the virtual tour’s many features is an interactive, aerial map of the 32 buildings on our Bethesda campus. By clicking on a highlighted building, you can explore an impressive multimedia gallery of photos, video clips, and other resources. The tour will allow you to learn more about NIH and the ways in which we help people live longer and healthier lives.

You also can learn more about NIH’s 27 Institutes and Centers, including the NIH Clinical Center and 20 other in-depth tour stops—from research labs to patient rooms—and hear directly from some of our impressive researchers, leaders, and patients. For example, you can learn about (https://www.nih.gov/virtual-tour/#ctdl-TOS_20220902134104494,UMAP_20220603185441371) chronic pain research from a lab in the NIH Clinical Center or see the largest (https://www.nichd.nih.gov/research/atNICHD/Investigators/weinstein/zebrafish) zebrafish facility in the world, housed in Building 6.

What I like most about the virtual tour is that it captures what makes NIH so special—the many amazing people who collaborate every day to discover ways to solve seemingly intractable research problems. I admire their commitment to follow the science wherever it may lead.

In fact, from its humble beginnings in a one-room laboratory in 1887, NIH has become the world’s largest funder of medical research, whether that’s mobilizing to combat a deadly pandemic or strategizing to help people with a rare disorder find answers.

Not only does NIH conduct groundbreaking research in its own labs and clinics, it also supports much of the medical research conducted at universities and institutions in your (https://reporter.nih.gov/) states and local communities. Whether in Bethesda or beyond the Beltway, this national research effort will continue to yield the needed understanding to turn discovery into better health, helping more people to flourish and lead fully productive lives, now and in the generations to come.

That’s certainly something we can all celebrate this holiday, the 247th birthday of our great nation that I’m so honored to serve. Have a great, but safe, Fourth of July, and I’ll see you back here soon to share another blog post and another story of NIH-supported research progress.

Links:

(https://www.nih.gov/virtual-tour/) Virtual Tour (NIH)

(https://www.nih.gov/about-nih/visitor-information) Visitor Information (NIH)

(https://history.nih.gov/) The Office of NIH History & Stetten Museum (NIH)

(https://directorsblog.nih.gov/2023/06/29/plans-for-new-cancer-center-in-kansas/) Plans for New Cancer Center in Kansas
Jun 29th 2023, 17:15

It was a pleasure to be in Kansas City and join U. S. Senator Jerry Moran of Kansas to celebrate progress toward the construction of a new building for the University of Kansas Cancer Center. The facility would centralize its current seven unique sites. As I witnessed firsthand, the strong community support for the new facility illustrates the power of a vibrant public-private partnership to enhance cancer care within the state.  That afternoon, I gathered with some of the event participants for this photo. Starting in the back row (l-r), you see Senator Moran; Rachel Pepper, chief nursing officer, Kansas City Division, The University of Kansas Health System; Roy Jensen, director, The University of Kansas Cancer Center, Kansas City; Bob Page, president and CEO, The University of Kansas Health System, Kansas City. In the front row (l-r) are Joseph McGuirk, Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Kansas City; Britany Leiker, nurse manager, The University of Kansas Medical Center, Kansas City; Tammy Peterman, president, Kansas City Division, The University of Kansas Health System; Doug Girod, chancellor, University of Kansas, Lawrence; and I’m next standing at the end of the row.  The event was held on June 27 at The University of Kansas Health Education Building, Kansas City. Credit: Elissa Monroe, The University of Kansas Medical Center, Kansas City. 

(https://directorsblog.nih.gov/2023/06/27/changes-in-human-microbiome-precede-alzheimers-cognitive-declines/) Changes in Human Microbiome Precede Alzheimer’s Cognitive Declines
Jun 27th 2023, 09:00

Caption: The human gut teems with bacteria and other microbes. They contribute to our health but also influence our susceptibility to certain diseases, including Alzheimer’s disease. Credit: Donny Bliss, NIH

In people with Alzheimer’s disease, the underlying changes in the brain associated with dementia typically begin many years—or even decades—before a diagnosis. While pinpointing (https://www.nia.nih.gov/health/what-causes-alzheimers-disease#factors) the exact causes of Alzheimer’s remains a major research challenge, they likely involve a combination of genetic, environmental, and lifestyle factors. Now an NIH-funded study elucidates the role of another likely culprit that you may not have considered: the human gut (https://www.genome.gov/genetics-glossary/Microbiome) microbiome, the trillions of diverse bacteria and other microbes that live primarily in our intestines [1].

Earlier studies had showed that the gut microbiomes of people with symptomatic Alzheimer’s disease differ from those of healthy people with normal cognition [2]. What this new work advances is that these differences arise early on in people who will develop Alzheimer’s, even before any obvious symptoms appear.

The science still has a ways to go before we’ll know if specific dietary changes can alter the gut microbiome and modify its influence on the brain in the right ways. But what’s exciting about this finding is it raises the possibility that doctors one day could test a patient’s stool sample to determine if what’s present from their gut microbiome correlates with greater early risk for Alzheimer’s dementia. Such a test would help doctors detect Alzheimer’s earlier and intervene sooner to slow or ideally even halt its advance.

The new findings, reported in the journal Science Translational Medicine, come from a research team led by Gautam Dantas and Beau Ances, Washington University School of Medicine, St. Louis. Ances is a clinician who treats and studies people with Alzheimer’s; Dantas is a basic researcher and expert on the gut microbiome. 

The pair struck up a conversation one day about the possible connection between the gut microbiome and Alzheimer’s. While they knew about the earlier studies suggesting a link, they were surprised that nobody had looked at the gut microbiomes of people in the earliest, so-called preclinical, stages of the disease. That’s when dementia isn’t detectable, but the brain has formed amyloid-beta plaques, which are associated with Alzheimer’s.

To take a look, they enrolled 164 healthy volunteers, age 68 to 94, who performed normally on standard tests of cognition. They also collected stool samples from each volunteer and thoroughly analyzed them all the microbes from their gut microbiome. Study participants also kept food diaries and underwent extensive testing, including two types of brain scans, to look for signs of amyloid-beta plaques and (https://directorsblog.nih.gov/2016/05/24/alzheimers-disease-tau-protein-predicts-early-memory-loss/) tau protein accumulation that precede the onset of Alzheimer’s symptoms.

Among the volunteers, about a third (49 individuals) unfortunately had signs of early Alzheimer’s disease. And, as it turned out, their microbiomes showed differences, too.

The researchers found that those with preclinical Alzheimer’s disease had markedly different assemblages of gut bacteria. Their microbiomes differed in many of the bacterial species present. Those species-level differences also point to differences in the way their microbiomes would be expected to function at a metabolic level. These microbiome changes were observed even though the individuals didn’t seem to have any apparent differences in their diets.

The team also found that the microbiome changes correlated with amyloid-beta and tau levels in the brain. But they did not find any relationship to degenerative changes in the brain, which tend to happen later in people with Alzheimer’s.

The team is now conducting a five-year study that will follow volunteers to get a better handle on whether the differences observed in the gut microbiome are a cause or a consequence of the brain changes seen in Alzheimer’s. If it’s a cause, this discovery would raise the tantalizing possibility that specially formulated probiotics or (https://directorsblog.nih.gov/2014/10/21/you-wont-believe-whats-in-these-pills/) fecal transplants that promote the growth of “good” bacteria over “bad” bacteria in the gut might slow the development of Alzheimer’s and its most devastating symptoms. It’s an exciting area of research and definitely one worth following in the years ahead.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37315112/) Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease. Ferreiro AL, Choi J, Ryou J, Newcomer EP, Thompson R, Bollinger RM, Hall-Moore C, Ndao IM, Sax L, Benzinger TLS, Stark SL, Holtzman DM, Fagan AM, Schindler SE, Cruchaga C, Butt OH, Morris JC, Tarr PI, Ances BM, Dantas G. Sci Transl Med. 2023 Jun 14;15(700):eabo2984. doi: 10.1126/scitranslmed.abo2984. Epub 2023 Jun 14. PMID: 37315112.

[2] (https://pubmed.ncbi.nlm.nih.gov/29051531/) Gut microbiome alterations in Alzheimer’s disease. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Sci Rep. 2017 Oct 19;7(1):13537. doi: 10.1038/s41598-017-13601-y. PMID: 29051531; PMCID: PMC5648830.

Links:

(https://www.nia.nih.gov/health/alzheimers) Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Video: (https://www.youtube.com/watch?v=0GXv3mHs9AU) How Alzheimer’s Changes the Brain (NIA)

(http://www.dantaslab.org) Dantas Lab (Washington University School of Medicine. St. Louis)

(https://anceslab.wustl.edu/people/beau-ances-md-phd/) Ances Bioimaging Laboratory (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases

(https://directorsblog.nih.gov/2023/06/20/immune-resilience-is-key-to-a-long-and-healthy-life/) Immune Resilience is Key to a Long and Healthy Life
Jun 20th 2023, 09:13

Caption: A new measure of immunity called immune resilience is helping researchers find clues as to why some people remain healthier even in the face of varied inflammatory stressors. Credit: Modified from Shutterstock/Ground Picture 

Do you feel as if you or perhaps your family members are constantly coming down with illnesses that drag on longer than they should? Or, maybe you’re one of those lucky people who rarely becomes ill and, if you do, recovers faster than others.

It’s clear that some people generally are more susceptible to infectious illnesses, while others manage to stay healthier or bounce back more quickly, sometimes even into old age. Why is this? A new study from an NIH-supported team has an intriguing answer [1]. The difference, they suggest, may be explained in part by a new measure of immunity they call immune resilience—the ability of the immune system to rapidly launch attacks that defend effectively against infectious invaders and respond appropriately to other types of inflammatory stressors, including aging or other health conditions, and then quickly recover, while keeping potentially damaging inflammation under wraps.

The findings in the journal Nature Communications come from an international team led by Sunil Ahuja, University of Texas Health Science Center and the Department of Veterans Affairs Center for Personalized Medicine, both in San Antonio. To understand the role of immune resilience and its effect on longevity and health outcomes, the researchers looked at multiple other studies including healthy individuals and those with a range of health conditions that challenged their immune systems.

By looking at multiple studies in varied infectious and other contexts, they hoped to find clues as to why some people remain healthier even in the face of varied inflammatory stressors, ranging from mild to more severe. But to understand how immune resilience influences health outcomes, they first needed a way to measure or grade this immune attribute.

The researchers developed two methods for measuring immune resilience. The first metric, a laboratory test called immune health grades (IHGs), is a four-tier grading system that calculates the balance between infection-fighting CD8+ and CD4+ T-cells. IHG-I denotes the best balance tracking the highest level of resilience, and IHG-IV denotes the worst balance tracking the lowest level of immune resilience. An imbalance between the levels of these T cell types is observed in many people as they age, when they get sick, and in people with autoimmune diseases and other conditions.

The researchers also developed a second metric that looks for two patterns of expression of a select set of genes. One pattern associated with survival and the other with death. The survival-associated pattern is primarily related to immune competence, or the immune system’s ability to function swiftly and restore activities that encourage disease resistance. The mortality-associated genes are closely related to inflammation, a process through which the immune system eliminates pathogens and begins the healing process but that also underlies many disease states.

Their studies have shown that high expression of the survival-associated genes and lower expression of mortality-associated genes indicate optimal immune resilience, correlating with a longer lifespan. The opposite pattern indicates poor resilience and a greater risk of premature death. When both sets of genes are either low or high at the same time, immune resilience and mortality risks are more moderate.

In the newly reported study initiated in 2014, Ahuja and his colleagues set out to assess immune resilience in a collection of about 48,500 people, with or without various acute, repetitive, or chronic challenges to their immune systems. In an earlier study, the researchers showed that this novel way to measure immune status and resilience predicted hospitalization and mortality during acute COVID-19 across a wide age spectrum [2].

The investigators have analyzed stored blood samples and publicly available data representing people, many of whom were healthy volunteers, who had enrolled in different studies conducted in Africa, Europe, and North America. Volunteers ranged in age from 9 to 103 years. They also evaluated participants in the Framingham Heart Study, a long-term effort to identify common factors and characteristics that contribute to cardiovascular disease.

To examine people with a wide range of health challenges and associated stresses on their immune systems, the team also included participants who had influenza or COVID-19, and people living with HIV. They also included kidney transplant recipients, people with lifestyle factors that put them at high risk for sexually transmitted infections, and people who’d had sepsis, a condition in which the body has an extreme and life-threatening response following an infection.

The question in all these contexts was the same: How well did the two metrics of immune resilience predict an individual’s health outcomes and lifespan? The short answer is that immune resilience, longevity, and better health outcomes tracked together well. Those with metrics indicating optimal immune resilience generally had better health outcomes and lived longer than those who had lower scores on the immunity grading scale. Indeed, those with optimal immune resilience were more likely to:

Live longer,

Resist HIV infection or the progression from HIV to AIDS,

Resist symptomatic influenza,

Resist a recurrence of skin cancer after a kidney transplant,

Survive COVID-19, and

Survive sepsis.

The study also revealed other interesting findings. While immune resilience generally declines with age, some people maintain higher levels of immune resilience as they get older for reasons that aren’t yet known, according to the researchers. Some people also maintain higher levels of immune resilience despite the presence of inflammatory stress to their immune systems such as during HIV infection or acute COVID-19. People of all ages can show high or low immune resilience. The study also found that higher immune resilience is more common in females than it is in males.

The findings suggest that there is a lot more to learn about why people differ in their ability to preserve optimal immune resilience. With further research, it may be possible to develop treatments or other methods to encourage or restore immune resilience as a way of improving general health, according to the study team.

The researchers suggest it’s possible that one day checkups of a person’s immune resilience could help us to understand and predict an individual’s health status and risk for a wide range of health conditions. It could also help to identify those individuals who may be at a higher risk of poor outcomes when they do get sick and may need more aggressive treatment. Researchers may also consider immune resilience when designing vaccine clinical trials.

A more thorough understanding of immune resilience and discovery of ways to improve it may help to address important health disparities linked to differences in race, ethnicity, geography, and other factors. We know that healthy eating, exercising, and taking precautions to avoid getting sick foster good health and longevity; in the future, perhaps we’ll also consider how our immune resilience measures up and take steps to achieve or maintain a healthier, more balanced, immunity status.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37311745/) Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Ahuja SK, Manoharan MS, Lee GC, McKinnon LR, Meunier JA, Steri M, Harper N, Fiorillo E, Smith AM, Restrepo MI, Branum AP, Bottomley MJ, Orrù V, Jimenez F, Carrillo A, Pandranki L, Winter CA, Winter LA, Gaitan AA, Moreira AG, Walter EA, Silvestri G, King CL, Zheng YT, Zheng HY, Kimani J, Blake Ball T, Plummer FA, Fowke KR, Harden PN, Wood KJ, Ferris MT, Lund JM, Heise MT, Garrett N, Canady KR, Abdool Karim SS, Little SJ, Gianella S, Smith DM, Letendre S, Richman DD, Cucca F, Trinh H, Sanchez-Reilly S, Hecht JM, Cadena Zuluaga JA, Anzueto A, Pugh JA; South Texas Veterans Health Care System COVID-19 team; Agan BK, Root-Bernstein R, Clark RA, Okulicz JF, He W. Nat Commun. 2023 Jun 13;14(1):3286. doi: 10.1038/s41467-023-38238-6. PMID: 37311745.

[2] (https://pubmed.ncbi.nlm.nih.gov/34508765/) Immunologic resilience and COVID-19 survival advantage. Lee GC, Restrepo MI, Harper N, Manoharan MS, Smith AM, Meunier JA, Sanchez-Reilly S, Ehsan A, Branum AP, Winter C, Winter L, Jimenez F, Pandranki L, Carrillo A, Perez GL, Anzueto A, Trinh H, Lee M, Hecht JM, Martinez-Vargas C, Sehgal RT, Cadena J, Walter EA, Oakman K, Benavides R, Pugh JA; South Texas Veterans Health Care System COVID-19 Team; Letendre S, Steri M, Orrù V, Fiorillo E, Cucca F, Moreira AG, Zhang N, Leadbetter E, Agan BK, Richman DD, He W, Clark RA, Okulicz JF, Ahuja SK. J Allergy Clin Immunol. 2021 Nov;148(5):1176-1191. doi: 10.1016/j.jaci.2021.08.021. Epub 2021 Sep 8. PMID: 34508765; PMCID: PMC8425719.

Links:

(https://covid19.nih.gov/) COVID-19 Research (NIH)

(https://hivinfo.nih.gov/home-page) HIV Info (NIH)

(https://nigms.nih.gov/education/fact-sheets/Pages/sepsis.aspx#:~:text=Sepsis%20occurs%20unpredictably%20and%20can,and%20the%20patient%20can%20die) Sepsis (National Institute of General Medical Sciences/NIH)

(https://www.uthscsa.edu/patient-care/physicians/providers/1417064585/Sunil-Ahuja) Sunil Ahuja (University of Texas Health Science Center, San Antonio)

(https://www.framinghamheartstudy.org/) Framingham Heart Study (National Heart, Lung, and Blood Institute/NIH)

“(https://www.niaid.nih.gov/news-events/secret-health-long-life-immune-resilience-niaid-grantees) A Secret to Health and Long Life? Immune Resilience, NIAID Grantees Report,” NIAID Now Blog, June 13, 2023

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute on Aging; National Institute of Mental Health; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute

(https://directorsblog.nih.gov/2023/06/13/mapping-immune-cell-neighborhoods-in-psoriasis-to-understand-its-course/) Mapping Immune Cell “Neighborhoods” in Psoriasis to Understand its Course
Jun 13th 2023, 12:00

Researchers mapped immune cell “neighborhoods” in the skin of people with psoriasis compared to the healthy skin of people without psoriasis to learn more about the disease course and why it comes with more risk for other health problems. Credit: Donny Bliss, NIH

“Location, location, location.” While most of us know this phrase as a real estate adage, location—specifically that of various cell types—is becoming a key area of investigation in studying human disease. New techniques are enabling scientists to understand where certain cells are with respect to one another and how changes in their activity may affect your overall health.

In one recent example of the power of this approach, NIH-funded researchers [1] used a sophisticated method to map immune cells within human skin to get a more detailed picture of psoriasis, a common, chronic disease in which the immune system becomes overactive leading to skin inflammation. People with psoriasis develop patches of itchy, red, and flaky lesions on their skin, which can be mild to severe. For reasons that aren’t entirely clear, they’re also at (https://www.niams.nih.gov/health-topics/psoriasis) higher risk for developing a wide range of other health conditions, including a unique form of arthritis known as psoriatic arthritis, diabetes, mental health issues, heart problems, and more.

The hope is that these newly drawn, precise maps of cellular “neighborhoods” in human skin will help chart the precise course of this disease to understand better the differences between mild and more severe forms. They may also yield important clues as to why people with psoriasis develop other health problems more often than people without psoriasis.

In the new study, a team including Jose Scher and Shruti Naik, NYU Langone, New York, analyzed immune cells within 25 skin samples from 14 volunteers, including those with active psoriasis, those with psoriasis but no active lesions, and people with healthy skin who do not have psoriasis. The researchers relied on a sophisticated approach called spatial transcriptomics [2] to map out what happens at the single-cell level within the samples.

In earlier approaches to single-cell analysis, researchers first would separate cells from the tissue they came from. While they could measure gene activity within those cells at the individual level, they couldn’t put things back together to see how they all fit. With spatial transcriptomics, it’s now possible to molecularly profile single cells to measure their activity in a tissue sample while also mapping their locations with respect to other cells.

The new study led to some intriguing findings. For instance, certain immune cells, specifically B cells, moved to the upper layers of the skin during active disease. That’s notable because prior studies had been unable to capture B cells in the skin adequately, and these cells are thought to play an important role in the disease.

Interestingly, the spatial cellular maps revealed inflammatory regions in both actively inflamed skin and in skin that appeared healthy. This finding highlights the fact that the inflammation that goes with psoriasis can affect the skin, and likely other parts of the body, in ways that aren’t easily observed. In future studies, the researchers want to explore how the presence of psoriasis and its underlying changes in immune cell activity may influence other organs and tissues beneath the skin.

Their fine-scale maps also showed increased gene activity in dozens of molecular pathways that are tied to metabolism and the control of lipid levels. That’s especially interesting because these factors are known to go awry in diabetes and heart conditions, which happen more often in people with psoriasis compared to those without. They also could see in their maps that this altered activity sometimes occurred in clear skin distant from any apparent lesions.

Having discovered such signals with potential consequences for other parts of the body, the researchers report that they’re working to understand how inflammatory immune cells and processes in the skin may lead to more widespread disease processes that affect other parts of the body. They plan to conduct similar studies in larger groups of people with and without active psoriasis lesions and studies following individuals with psoriasis over time. They’ll also explore questions about why people respond differently to the same anti-inflammatory treatment regimens.

To speed the process of discovery, they’ve made their maps and associated data freely available as a (https://zenodo.org/record/7813973) resource for the scientific community. About 7.5 million adults in the U.S. and millions more worldwide have psoriasis and associated psoriatic conditions [3]. The hope is that these maps will one day help to steer them toward a healthier future.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37267384/) Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems. Castillo RL, Sidhu I, Dolgalev I, Chu T, Prystupa A, Subudhi I, Yan D, Konieczny P, Hsieh B, Haberman RH, Selvaraj S, Shiomi T, Medina R, Girija PV, Heguy A, Loomis CA, Chiriboga L, Ritchlin C, Garcia-Hernandez ML, Carucci J, Meehan SA, Neimann AL, Gudjonsson JE, Scher JU, Naik S. Sci Immunol. 2023 Jun 8;8(84):eabq7991. doi: 10.1126/sciimmunol.abq7991.

[2] (https://pubmed.ncbi.nlm.nih.gov/33408395/) Method of the Year: spatially resolved transcriptomics. Marx V. Nat Methods. 2021 Jan;18(1):9-14. doi: 10.1038/s41592-020-01033-y.

[3] (https://pubmed.ncbi.nlm.nih.gov/34190957/) Psoriasis Prevalence in Adults in the United States. Armstrong AW, Mehta MD, Schupp CW, Gondo GC, Bell SJ, Griffiths CEM. JAMA Dermatol. 2021 Aug 1;157(8):940-946. doi: 10.1001/jamadermatol.2021.2007.

Links:

(https://www.niams.nih.gov/health-topics/psoriasis) Psoriasis (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)

(https://nyulangone.org/doctors/1609073303/jose-u-scher) Jose Scher (NYU Langone Health, New York, NY)

(https://med.nyu.edu/faculty/shruti-naik) Shruti Naik (NYU Langone Health, New York, NY)

NIH Support: National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases

(https://directorsblog.nih.gov/2023/06/06/encouraging-first-in-human-results-for-a-promising-hiv-vaccine/) Encouraging First-in-Human Results for a Promising HIV Vaccine
Jun 6th 2023, 09:00

Researchers used a customized nanoparticle (top left) to learn more about guiding the immune system to mount a desired robust response, the type needed for an effective HIV vaccine. Credit: Donny Bliss, NIH

In recent years, we’ve witnessed some truly inspiring progress in vaccine development. That includes the (https://directorsblog.nih.gov/2020/07/16/researchers-publish-encouraging-early-data-on-covid-19-vaccine/) mRNA vaccines that were so critical during the COVID-19 pandemic, the first approved vaccine for (https://www.niaid.nih.gov/news-events/nih-celebrates-fda-approval-rsv-vaccine-people-60-years-age-and-older) respiratory syncytial virus (RSV), and a “universal flu vaccine” candidate that could one day help to thwart future outbreaks of more novel (https://directorsblog.nih.gov/2022/12/06/experimental-mrna-vaccine-may-protect-against-all-20-influenza-virus-subtypes/) influenza viruses.

Inspiring progress also continues to be made toward a safe and effective vaccine for HIV, which still infects about 1.5 million people around the world each year [1]. A prime example is the recent first-in-human trial of an HIV vaccine made in the lab from a unique protein nanoparticle, a molecular construct measuring just (https://www.nih.gov/research-training/nanotechnology-nih) a few billionths of a meter.

The results of this early phase clinical study, published recently in the journal Science Translational Medicine [2] and earlier in Science [3], showed that the experimental HIV nanoparticle vaccine is safe in people. While this vaccine alone will not offer HIV protection and is intended to be part of an eventual broader, multistep vaccination regimen, the researchers also determined that it elicited a robust immune response in nearly all 36 healthy adult volunteers.

How robust? The results show that the nanoparticle vaccine, known by the lab name (https://directorsblog.nih.gov/2016/04/05/aids-vaccine-research-better-by-design/) eOD-GT8 60-mer, successfully expanded production of a rare type of antibody-producing immune B cell in nearly all recipients.

What makes this rare type of B cell so critical is that it is the cellular precursor of other B cells capable of producing broadly neutralizing antibodies (bnAbs) to protect against diverse HIV variants. Also very good news, the vaccine elicited broad responses from helper T cells. They play a critical supportive role for those essential B cells and their development of the needed broadly neutralizing antibodies.

For decades, researchers have brought a wealth of ideas to bear on developing a safe and effective HIV vaccine. However, crossing the finish line—an FDA-approved vaccine—has proved profoundly difficult.

A major reason is the human immune system is ill equipped to recognize HIV and produce the needed infection-fighting antibodies. And yet the medical literature includes reports of people with HIV who have produced the needed antibodies, showing that our immune system can do it.

But these people remain relatively rare, and the needed robust immunity clocks in only after many years of infection. On top of that, HIV has a habit of mutating rapidly to produce a wide range of identity-altering variants. For a vaccine to work, it most likely will need to induce the production of bnAbs that recognize and defend against not one, but the many different faces of HIV.

To make the uncommon more common became the quest of a research team that includes scientists William Schief, Scripps Research and IAVI Neutralizing Antibody Center, La Jolla, CA; M. Juliana McElrath, Fred Hutchinson Cancer Center, Seattle; and Kristen Cohen, a former member of the McElrath lab now at Moderna, Cambridge, MA. The team, with NIH collaborators and support, has been plotting out a stepwise approach to train the immune system into making the needed bnAbs that recognize many HIV variants.

The critical first step is to prime the immune system to make more of those coveted bnAb-precursor B cells. That’s where the protein nanoparticle known as eOD-GT8 60-mer enters the picture.

This nanoparticle, administered by injection, is designed to mimic a small, highly conserved segment of an HIV protein that allows the virus to bind and infect human cells. In the body, those nanoparticles launch an immune response and then quickly vanish. But because this important protein target for HIV vaccines is so tiny, its signal needed amplification for immune system detection.

To boost the signal, the researchers started with a bacterial protein called lumazine synthase (LumSyn). It forms the scaffold, or structural support, of the self-assembling nanoparticle. Then, they added to the LumSyn scaffold 60 copies of the key HIV protein. This louder HIV signal is tailored to draw out and engage those very specific B cells with the potential to produce bnAbs.

As the first-in-human study showed, the nanoparticle vaccine was safe when administered twice to each participant eight weeks apart. People reported only mild to moderate side effects that went away in a day or two. The vaccine also boosted production of the desired B cells in all but one vaccine recipient (35 of 36). The idea is that this increase in essential B cells sets the stage for the needed additional steps—booster shots that can further coax these cells along toward making HIV protective bnAbs.

The latest finding in Science Translational Medicine looked deeper into the response of helper T cells in the same trial volunteers. Again, the results appear very encouraging. The researchers observed CD4 T cells specific to the HIV protein and to the LumSyn in 84 percent and 93 percent of vaccine recipients. Their analyses also identified key hotspots that the T cells recognized, which is important information for refining future vaccines to elicit helper T cells.

The team reports that they’re now collaborating with Moderna, the developer of one of the two successful mRNA-based COVID-19 vaccines, on an mRNA version of eOD-GT8 60-mer. That’s exciting because mRNA vaccines are much faster and easier to produce and modify, which should now help to move this line of research along at a faster clip.

Indeed, two International AIDS Vaccine Initiative (IAVI)-sponsored clinical trials of the mRNA version are already underway, one in the U.S. and the other in Rwanda and South Africa [4]. It looks like this team and others are now on a promising track toward following the basic science and developing a multistep HIV vaccination regimen that guides the immune response and its stepwise phases in the right directions.

As we look back on more than 40 years of HIV research, it’s heartening to witness the progress that continues toward ending the HIV epidemic. This includes the recent FDA approval of the drug (https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-prevention) Apretude, the first injectable treatment option for pre-exposure prevention of HIV, and the continued global commitment to produce a safe and effective vaccine.

References:

[1] (https://www.unaids.org/en/resources/fact-sheet) Global HIV & AIDS statistics fact sheet. UNAIDS.

[2] (https://pubmed.ncbi.nlm.nih.gov/37224227/) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Cohen KW, De Rosa SC, Fulp WJ, deCamp AC, Fiore-Gartland A, Laufer DS, Koup RA, McDermott AB, Schief WR, McElrath MJ. Sci Transl Med. 2023 May 24;15(697):eadf3309.

[3] (https://pubmed.ncbi.nlm.nih.gov/36454825/) Vaccination induces HIV broadly neutralizing antibody precursors in humans. Leggat DJ, Cohen KW, Willis JR, Fulp WJ, deCamp AC, Koup RA, Laufer DS, McElrath MJ, McDermott AB, Schief WR. Science. 2022 Dec 2;378(6623):eadd6502.

[4] (https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-first-in-africa-clinical-trial-of-mrna-hiv-vaccine-development-program) IAVI and Moderna launch first-in-Africa clinical trial of mRNA HIV vaccine development program. IAVI. May 18, 2022.

Links:

(https://www.nih.gov/news-events/nih-research-matters/progress-toward-eventual-hiv-vaccine) Progress Toward an Eventual HIV Vaccine, NIH Research Matters, Dec. 13, 2022.

(https://www.niaid.nih.gov/news-events/nih-statement-hiv-vaccine-awareness-day-2023) NIH Statement on HIV Vaccine Awareness Day 2023, Auchincloss H, Kapogiannis, B. May, 18, 2023.  

(https://www.niaid.nih.gov/diseases-conditions/hiv-vaccine-development) HIV Vaccine Development (National Institute of Allergy and Infectious Diseases/NIH)

(https://www.iavi.org/) International AIDS Vaccine Initiative (IAVI) (New York, NY)

(https://www.scripps.edu/faculty/schief/) William Schief (Scripps Research, La Jolla, CA)

(https://www.fredhutch.org/en/faculty-lab-directory/mcelrath-julie.html) Julie McElrath (Fred Hutchinson Cancer Center, Seattle, WA)

(https://research.fredhutch.org/mcelrath/en.html?_ga=2.46930606.801930831.1685552534-1429204226.1685125743) McElrath Lab (Fred Hutchinson Cancer Center, Seattle, WA)

NIH Support: National Institute of Allergy and Infectious Diseases

(https://directorsblog.nih.gov/2023/05/30/case-study-unlocks-clues-to-rare-resilience-to-alzheimers-disease/) Case Study Unlocks Clues to Rare Resilience to Alzheimer’s Disease
May 30th 2023, 09:00

(https://directorsblog.nih.gov/wp-content/uploads/2023/05/Alzheimers-resistant-brain-post.jpg) Caption: Newly discovered Reelin-COLBOS gene variation may delay or prevent Alzheimer’s disease. Credit: Donny Bliss, NIH

Biomedical breakthroughs most often involve slow and steady research in studies involving large numbers of people. But sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications.

An NIH-funded case study published recently in the journal Nature Medicine falls into this far-reaching category [1]. The report highlights the world’s second person known to have an extreme resilience to a rare genetic form of early onset Alzheimer’s disease. These latest findings in a single man follow a 2019 report of a woman with similar resilience to developing symptoms of Alzheimer’s despite having the same strong genetic predisposition for the disease [2].

The new findings raise important new ideas about the series of steps that may lead to Alzheimer’s and its dementia. They’re also pointing the way to key parts of the brain for cognitive resilience—and potentially new treatment targets—that may one day help to delay or even stop progression of Alzheimer’s.

The man in question is a member of a well-studied extended family from the country of Colombia. This group of related individuals, or kindred, is the largest in the world with a genetic variant called the “Paisa” mutation (or Presenilin-1 E280A). This Paisa variant follows an autosomal dominant pattern of inheritance, meaning that those with a single altered copy of the rare variant passed down from one parent usually develop mild cognitive impairment around the age of 44. They typically advance to full-blown dementia around the age of 50 and rarely live past the age of 60. This contrasts with the (https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet) most common form of Alzheimer’s, which usually begins after age 65.

The new findings come from a team led by (https://directorsblog.nih.gov/2015/04/23/creative-minds-opening-a-window-on-alzheimers-before-it-strikes/) Yakeel Quiroz, Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Massachusetts Eye and Ear, Boston; Diego Sepulveda-Falla, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Francisco Lopera, University of Antioquia, Medellín, Colombia. Lopera (https://www.fic.nih.gov/News/Examples/Pages/alzheimers-brain-disorders-colombia.aspx) first identified this family more than 30 years ago and has been studying them ever since.

In the new case report, the researchers identified a Colombian man who’d been married with two children and retired from his job as a mechanic in his early 60s. Despite carrying the Paisa mutation, his first cognitive assessment at age 67 showed he was cognitively intact, having limited difficulties with verbal learning skills or language. It wasn’t until he turned 70 that he was diagnosed with mild cognitive impairment—more than 20 years later than the expected age for this family—showing some decline in short-term memory and verbal fluency.

At age 73, he enrolled in the (https://mapp.mgh.harvard.edu/projects/colbos/) Colombia-Boston biomarker research study (COLBOS). This study is a collaborative project between the University of Antioquia and Massachusetts General Hospital involving approximately 6,000 individuals from the Paisa kindred. About 1,500 of those in the study carry the mutation that sets them up for early Alzheimer’s. As a member of the COLBOS study, the man underwent thorough neuroimaging tests to look for amyloid plaques and tau tangles, both of which are hallmarks of Alzheimer’s.

While this man died at age 74 with Alzheimer’s, the big question is: how did he stave off dementia for so long despite his poor genetic odds? The COLBOS study earlier identified a woman with a similar resilience to Alzheimer’s, which they traced to two copies of a rare, protective genetic variant called Christchurch. This variant affects a gene called apolipoprotein E (APOE3), which is well known for its influence on Alzheimer’s risk. However, the man didn’t carry this same protective variant.

The researchers still thought they’d find an answer in his genome and kept looking. While they found several variants of possible interest, they zeroed in on a single gene variant that they’ve named Reelin-COLBOS. What helped them to narrow it down to this variant is the man also had a sister with the Paisa mutation who only progressed to advanced dementia at age 72. It turned out, in addition to the Paisa variant, the siblings also shared an altered copy of the newly discovered Reelin-COLBOS variant.

This Reelin-COLBOS gene is known to encode a protein that controls signals to chemically modify (https://directorsblog.nih.gov/2016/05/24/alzheimers-disease-tau-protein-predicts-early-memory-loss/) tau proteins, which form tangles that build up over time in the Alzheimer’s brain and have been linked to memory loss. Reelin is also functionally related to APOE, the gene that was altered in the woman with extreme Alzheimer’s protection. Reelin and APOE both interact with common protein receptors in neurons. Together, the findings add to evidence that signaling pathways influencing tau play an important role in Alzheimer’s pathology and protection.

The neuroimaging exams conducted when the man was age 73 have offered further intriguing clues. They showed that his brain had extensive amyloid plaques. He also had tau tangles in some parts of his brain. But one brain region, called the entorhinal cortex, was notable for having a very minimal amount of those hallmark tau tangles.

The entorhinal cortex is a hub for memory, navigation, and the perception of time. Its degeneration also leads to cognitive impairment and dementia. Studies of the newly identified Reelin-COLBOS variant in Alzheimer’s mouse models also help to confirm that the variant offers its protection by diminishing the pathological modifications of tau.

Overall, the findings in this one individual and his sister highlight the Reelin pathway and brain region as promising targets for future study and development of Alzheimer’s treatments. Quiroz and her colleagues report that they are actively exploring treatment approaches inspired by the Christchurch and Reelin-COLBOS discoveries.

Of course, there’s surely more to discover from continued study of these few individuals and others like them. Other as yet undescribed genetic and environmental factors are likely at play. But the current findings certainly offer some encouraging news for those at risk for Alzheimer’s disease—and a reminder of how much can be learned from careful study of remarkable individuals.

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37188781/) Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Lopera F, Marino C, Chandrahas AS, O’Hare M, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT, et al. Nat Med. 2023 May;29(5):1243-1252.

[2] (https://pubmed.ncbi.nlm.nih.gov/31686034/) Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Tariot PN, Johnson KA, Reiman EM, Quiroz YT et al. Nat Med. 2019 Nov;25(11):1680-1683.

Links:

(https://www.nia.nih.gov/health/alzheimers) Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)

“(https://www.fic.nih.gov/News/Examples/Pages/alzheimers-brain-disorders-colombia.aspx) NIH Support Spurs Alzheimer’s Research in Colombia,” Global Health Matters, January/February 2014, Fogarty International Center/NIS

“(https://nihrecord.nih.gov/2022/08/19/colbos-study-reveals-mysteries-alzheimer-s-disease) COLBOS Study Reveals Mysteries of Alzheimer’s Disease,” NIH Record, August 19, 2022.

(https://mapp.mgh.harvard.edu/yakeel-quiroz/) Yakeel Quiroz (Massachusetts General Hospital, Harvard Medical School, Boston)

(https://researchers.masseyeandear.org/details/278/joseph-arboleda-velasquez) Joseph Arboleda-Velasquez (Massachusetts Eye and Ear, Harvard Medical School, Boston)

(https://molneup-ad.org) Diego Sepulveda-Falla Lab (University Medical Center Hamburg-Eppendorf, Hamburg, Germany)

(https://scholar.google.com/citations?user=dVMs_nEAAAAJ&hl=en) Francisco Lopera (University of Antioquia, Medellín, Colombia)

NIH Support: National Institute on Aging; National Eye Institute; National Institute of Neurological Disorders and Stroke; Office of the Director

(https://directorsblog.nih.gov/2023/05/23/basic-researchers-discover-possible-target-for-treating-glioblastoma/) Basic Researchers Discover Possible Target for Treating Brain Cancer
May 23rd 2023, 09:00

Caption: Illustration of cancer cell (bottom right) stealing mitochondria (white ovals)  from a healthy astrocyte cell (left). Credit: Donny Bliss/NIH

Over the years, cancer researchers have uncovered many of the tricks that tumors use to fuel their growth and evade detection by the body’s immune system. More tricks await discovery, and finding them will be key in learning to target the right treatments to the right cancers.

Recently, a team of researchers demonstrated in lab studies a surprising trick pulled off by cells from a common form of brain cancer called (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/glioblastoma) glioblastoma. The researchers found that glioblastoma cells steal (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mitochondria) mitochondria, the power plants of our cells, from other cells in the central nervous system [1].

Why would cancer cells do this? How do they pull it off? The researchers don’t have all the answers yet. But glioblastoma arises from abnormal (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/astrocyte) astrocytes, a particular type of the (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/glial-cell) glial cell, a common cell in the brain and spinal cord. It seems from their initial work that stealing mitochondria from neighboring normal cells help these transformed glioblastoma cells to ramp up their growth. This trick might also help to explain why glioblastoma is one of the most aggressive forms of primary brain cancer, with limited treatment options.

In the new study, published in the journal Nature Cancer, a team co-led by Justin Lathia, Lerner Research Institute, Cleveland Clinic, OH, and Hrvoje Miletic, University of Bergen, Norway, had noticed some earlier studies suggesting that glioblastoma cells might steal mitochondria. They wanted to take a closer look.

This very notion highlights an emerging and much more dynamic view of mitochondria. Scientists used to think that mitochondria—which can number in the thousands within a single cell—generally just stayed put. But recent research has established that mitochondria can move around within a cell. They sometimes also get passed from one cell to another.

It also turns out that the intercellular movement of mitochondria has many implications for health. For instance, the transfer of mitochondria helps to rescue damaged tissues in the central nervous system, heart, and respiratory system. But, in other circumstances, this process may possibly come to the rescue of cancer cells.

While Lathia, Miletic, and team knew that mitochondrial transfer was possible, they didn’t know how relevant or dangerous it might be in brain cancers. To find out, they studied mice implanted with glioblastoma tumors from other mice or people with glioblastoma. This mouse model also had been modified to allow the researchers to trace the movement of mitochondria.

Their studies show that healthy cells often transfer some of their mitochondria to glioblastoma cells. They also determined that those mitochondria often came from healthy astrocytes, a process that had been seen before in the recovery from a stroke.

But the transfer process isn’t easy. It requires that a cell expend a lot of energy to form (https://directorsblog.nih.gov/2018/11/29/the-actin-superhighway/) actin filaments that contract to pull the mitochondria along. They also found that the process depends on growth-associated protein 43 (GAP43), suggesting that future treatments aimed at this protein might help to thwart the process.

Their studies also show that, after acquiring extra mitochondria, glioblastoma cells shift into higher gear. The cancerous cells begin burning more energy as their metabolic pathways show increased activity. These changes allow for more rapid and aggressive growth. Overall, the findings show that this interaction between healthy and cancerous cells may partly explain why glioblastomas are so often hard to beat.

While more study is needed to confirm the role of this process in people with glioblastoma, the findings are an important reminder that treatment advances in oncology may come not only from study of the cancer itself but also by carefully considering the larger context and environments in which tumors grow. The hope is that these intriguing new findings will one day lead to new treatment options for the approximately 13,000 people in the U.S. alone who are diagnosed with glioblastoma each year [2].

References:

[1] (https://pubmed.ncbi.nlm.nih.gov/37169842/) GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity. Watson DC, Bayik D, Storevik S, Moreino SS,  Hjelmeland AB, Hossain JA, Miletic H, Lathia JD et al. Nat Cancer. 2023 May 11. [Published online ahead of print.]

[2] (https://pubmed.ncbi.nlm.nih.gov/30445539/) CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. 2018 Oct 1, Neuro Oncol., p. 20(suppl_4):iv1-iv86.

Links:

(https://rarediseases.info.nih.gov/diseases/2491/glioblastoma) Glioblastoma (National Center for Advancing Translational Sciences/NIH)

(https://www.cancer.gov/types/brain) Brain Tumors (National Cancer Institute/NIH)

(https://www.lerner.ccf.org/cardiovascular-metabolic/lathia/) Justin Lathia Lab (Cleveland Clinic, OH)

(https://www.uib.no/en/rg/mic/76532/prof-hrvoje-miletic-experimental-neuro-oncology-neuropathology) Hrvoje Miletic (University of Bergen, Norway)

NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Allergy and Infectious Diseases

(https://directorsblog.nih.gov/2023/05/18/groundbreaking-at-nih-clinical-center/) Groundbreaking at NIH Clinical Center
May 18th 2023, 16:54

(https://directorsblog.nih.gov/wp-content/uploads/2023/05/2023-05-16-SRLM-Groundbreaking-006.jpg) So glad to take part in the May 16 groundbreaking for the Surgery, Radiology and Laboratory Medicine (SRLM) wing of the NIH Clinical Center. The expansive new wing will house: the Department of Perioperative Medicine; Department of Radiology and Imaging Sciences, Department of Laboratory Medicine, the National Heart, Lung, and Blood Institute’s Cardiovascular Intervention Program; several National Cancer Institute laboratories; and patient service areas. As shown here at the podium, we were honored to be joined by Andrea Palm, deputy secretary, U.S. Department of Health and Human Services. Also pictured (left to right): Dan Wheeland, NIH associate director for Research Facilities; Nina Schor, NIH deputy director for Intramural Research; James Gilman NIH Clinical Center CEO; me; Steven Rosenberg, chief, Surgery Branch, National Cancer Institute; and Alfred Johnson, NIH deputy director for Management. Modernizing the Clinical Center will help to ensure that this amazing facility continues to provide high quality patient care alongside cutting-edge biomedical research. Credit: Chia-Chi Charlie Chang, NIH

Forwarded by:
Michael Reeder LCPC
Baltimore, MD

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