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Taking a Closer Look at COVID-19’s Effects on the Brain

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MRI of a brain damaged by COVID-19
Caption: Magnetic resonance microscopy showing lower part of a COVID-19 patient’s brain stem postmortem. Arrows point to light and dark spots indicative of blood vessel damage with no signs of infection by the coronavirus that causes COVID-19. Credit: National Institute of Neurological Disorders and Stroke, NIH

While primarily a respiratory disease, COVID-19 can also lead to neurological problems. The first of these symptoms might be the loss of smell and taste, while some people also may later battle headaches, debilitating fatigue, and trouble thinking clearly, sometimes referred to as “brain fog.” All of these symptoms have researchers wondering how exactly the coronavirus that causes COVID-19, SARS-CoV-2, affects the human brain.

In search of clues, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have now conducted the first in-depth examinations of human brain tissue samples from people who died after contracting COVID-19. Their findings, published in the New England Journal of Medicine, suggest that COVID-19’s many neurological symptoms are likely explained by the body’s widespread inflammatory response to infection and associated blood vessel injury—not by infection of the brain tissue itself [1].

The NIH team, led by Avindra Nath, used a high-powered magnetic resonance imaging (MRI) scanner (up to 10 times as sensitive as a typical MRI) to examine postmortem brain tissue from 19 patients. They ranged in age from 5 to 73, and some had preexisting conditions, such as diabetes, obesity, and cardiovascular disease.
The team focused on the brain’s olfactory bulb that controls our ability to smell and the brainstem, which regulates breathing and heart rate. Based on earlier evidence, both areas are thought to be highly susceptible to COVID-19.

Indeed, the MRI images revealed in both regions an unusual number of bright spots, a sign of inflammation. They also showed dark spots, which indicate bleeding. A closer look at the bright spots showed that tiny blood vessels in those areas were thinner than normal and, in some cases, leaked blood proteins into the brain. This leakage appeared to trigger an immune reaction that included T cells from the blood and the brain’s scavenging microglia. The dark spots showed a different pattern, with leaky vessels and clots but no evidence of an immune reaction.

While those findings are certainly interesting, perhaps equally noteworthy is what Nath and colleagues didn’t see in those samples. They could find no evidence in the brain tissue samples that SARS-CoV-2 had invaded the brain tissue. In fact, several methods to detect genetic material or proteins from the virus all turned up empty.

The findings are especially intriguing because there has been some suggestion based on studies in mice that SARS-CoV-2 might cross the blood-brain barrier and invade the brain. Indeed, a recent report by NIH-funded researchers in Nature Neuroscience showed that the viral spike protein, when injected into mice, readily entered the brain along with many other organs [2].

Another recent report in the Journal of Experimental Medicine, which used mouse and human brain tissue, suggests that SARS-CoV-2 may indeed directly infect the central nervous system, including the brain [3]. In autopsies of three people who died from complications of COVID-19, the NIH-supported researchers detected signs of SARS-CoV-2 in neurons in the brain’s cerebral cortex. This work was done using the microscopy-based technique of immunohistochemistry, which uses antibodies to bind to a target, in this case, the virus’s spike protein. Also last month, in a study published in the journal Neurobiology of Disease, another NIH-supported team demonstrated in a series of experiments in cell culture that the SARS-CoV-2 spike protein could cross a 3D model of the blood-brain barrier and infect the endothelial cells that line blood vessels in the brain [4].

Clearly, more research is needed, and NIH’s National Institute of Neurological Disorders and Stroke has just launched the COVID-19 Neuro Databank/Biobank (NeuroCOVID) to collect more clinical information, primarily about COVID-19-related neurological symptoms, complications, and outcomes. Meanwhile, Nath and colleagues continue to explore how COVID-19 affects the brain and triggers the neurological symptoms often seen in people with COVID-19. As we learn more about the many ways COVID-19 wreaks havoc on the body, understanding the neurological symptoms will be critical in helping people, including the so-called Long Haulers bounce back from this terrible viral infection.

References:

[1] Microvascular Injury in the Brains of Patients with Covid-19. Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. N Engl J Med. 2020 Dec 30.

[2] The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. Nat Neurosci. 2020 Dec 16.

[3] Neuroinvasion of SARS-CoV-2 in human and mouse brain. Song E, Zhang C, Israelow B, et al. J Exp Med (2021) 218 (3): e20202135.

[4] The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. Neurobiol Dis. 2020 Dec;146:105131.

Links:

COVID-19 Research (NIH)

Avindra Nath (National Institute of Neurological Disorders and Stroke/NIH)

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


The People’s Picks for Best Posts

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It’s 2021—Happy New Year! Time sure flies in the blogosphere. It seems like just yesterday that I started the NIH Director’s Blog to highlight recent advances in biology and medicine, many supported by NIH. Yet it turns out that more than eight years have passed since this blog got rolling and we are fast approaching my 1,000th post!

I’m pleased that millions of you have clicked on these posts to check out some very cool science and learn more about NIH and its mission. Thanks to the wonders of social media software, we’ve been able to tally up those views to determine each year’s most-popular post. So, I thought it would be fun to ring in the New Year by looking back at a few of your favorites, sort of a geeky version of a top 10 countdown or the People’s Choice Awards. It was interesting to see what topics generated the greatest interest. Spoiler alert: diet and exercise seemed to matter a lot! So, without further ado, I present the winners:

2013: Fighting Obesity: New Hopes from Brown Fat. Brown fat, one of several types of fat made by our bodies, was long thought to produce body heat rather than store energy. But Shingo Kajimura and his team at the University of California, San Francisco, showed in a study published in the journal Nature, that brown fat does more than that. They discovered a gene that acts as a molecular switch to produce brown fat, then linked mutations in this gene to obesity in humans.

What was also nice about this blog post is that it appeared just after Kajimura had started his own lab. In fact, this was one of the lab’s first publications. One of my goals when starting the blog was to feature young researchers, and this work certainly deserved the attention it got from blog readers. Since highlighting this work, research on brown fat has continued to progress, with new evidence in humans suggesting that brown fat is an effective target to improve glucose homeostasis.

2014: In Memory of Sam Berns. I wrote this blog post as a tribute to someone who will always be very near and dear to me. Sam Berns was born with Hutchinson-Gilford progeria syndrome, one of the rarest of rare diseases. After receiving the sad news that this brave young man had passed away, I wrote: “Sam may have only lived 17 years, but in his short life he taught the rest of us a lot about how to live.”

Affecting approximately 400 people worldwide, progeria causes premature aging. Without treatment, children with progeria, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease, on average in their early teens.

From interactions with Sam and his parents in the early 2000s, I started to study progeria in my NIH lab, eventually identifying the gene responsible for the disorder. My group and others have learned a lot since then. So, it was heartening last November when the Food and Drug Administration approved the first treatment for progeria. It’s an oral medication called Zokinvy (lonafarnib) that helps prevent the buildup of defective protein that has deadly consequences. In clinical trials, the drug increased the average survival time of those with progeria by more than two years. It’s a good beginning, but we have much more work to do in the memory of Sam and to help others with progeria. Watch for more about new developments in applying gene editing to progeria in the next few days.

2015: Cytotoxic T Cells on Patrol. Readers absolutely loved this post. When the American Society of Cell Biology held its first annual video competition, called CellDance, my blog featured some of the winners. Among them was this captivating video from Alex Ritter, then working with cell biologist Jennifer Lippincott-Schwartz of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The video stars a roving, specialized component of our immune system called cytotoxic T cells. Their job is to seek out and destroy any foreign or detrimental cells. Here, these T cells literally convince a problem cell to commit suicide, a process that takes about 10 minutes from detection to death.

These cytotoxic T cells are critical players in cancer immunotherapy, in which a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. Cancer immunotherapy remains a promising area of research that continues to progress, with a lot of attention now being focused on developing immunotherapies for common, solid tumors like breast cancer. Ritter is currently completing a postdoctoral fellowship in the laboratory of Ira Mellman, Genentech, South San Francisco. His focus has shifted to how cancer cells protect themselves from T cells. And video buffs—get this—Ritter says he’s now created even cooler videos that than the one in this post.

2016: Exercise Releases Brain-Healthy Protein. The research literature is pretty clear: exercise is good for the brain. In this very popular post, researchers led by Hyo Youl Moon and Henriette van Praag of NIH’s National Institute on Aging identified a protein secreted by skeletal muscle cells to help explore the muscle-brain connection. In a study in Cell Metabolism, Moon and his team showed that this protein called cathepsin B makes its way into the brain and after a good workout influences the development of new neural connections. This post is also memorable to me for the photo collage that accompanied the original post. Why? If you look closely at the bottom right, you’ll see me exercising—part of my regular morning routine!

2017: Muscle Enzyme Explains Weight Gain in Middle Age. The struggle to maintain a healthy weight is a lifelong challenge for many of us. While several risk factors for weight gain, such as counting calories, are within our control, there’s a major one that isn’t: age. Jay Chung, a researcher with NIH’s National Heart, Lung, and Blood Institute, and his team discovered that the normal aging process causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies showed it also slows down metabolism, making it more difficult to burn fat.

Since publishing this paper in Cell Metabolism, Chung has been busy trying to understand how aging increases the activity of DNA-PK and its ability to suppress renewal of the cell’s energy-producing mitochondria. Without renewal of damaged mitochondria, excess oxidants accumulate in cells that then activate DNA-PK, which contributed to the damage in the first place. Chung calls it a “vicious cycle” of aging and one that we’ll be learning more about in the future.

2018: Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic? This impressive bit of microbial detective work had blog readers clicking and commenting for several weeks. So, it’s no surprise that it was the runaway People’s Choice of 2018.

Clostridium difficile (C. diff) is a common bacterium that lives harmlessly in the gut of most people. But taking antibiotics can upset the normal balance of healthy gut microbes, allowing C. diff. to multiply and produce toxins that cause inflammation and diarrhea.

In the 2000s, C. diff. infections became far more serious and common in American hospitals, and Robert Britton, a researcher at Baylor College of Medicine, Houston, wanted to know why. He and his team discovered that two subtypes of C. diff have adapted to feed on the sugar trehalose, which was approved as a food additive in the United States during the early 2000s. The team’s findings, published in the journal Nature, suggested that hospitals and nursing homes battling C. diff. outbreaks may want to take a closer look at the effect of trehalose in the diet of their patients.

2019: Study Finds No Benefit for Dietary Supplements. This post that was another one that sparked a firestorm of comments from readers. A team of NIH-supported researchers, led by Fang Fang Zhang, Tufts University, Boston, found that people who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to amounts that are available from food consumption. The researchers based their conclusion on an analysis of the well-known National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010 survey data. The team, which reported its data in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess.

2020: Genes, Blood Type Tied to Risk of Severe COVID-19. Typically, my blog focuses on research involving many different diseases. That changed in 2020 due to the emergence of a formidable public health challenge: the coronavirus disease 2019 (COVID-19) pandemic. Since last March, the blog has featured 85 posts on COVID-19, covering all aspects of the research response and attracting more visitors than ever. And which post got the most views? It was one that highlighted a study, published last June in the New England Journal of Medicine, that suggested the clues to people’s variable responses to COVID-19 may be found in our genes and our blood types.

The researchers found that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death. The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system.

In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.

That’s it for the blog’s year-by-year Top Hits. But wait! I’d also like to give shout outs to the People’s Choice winners in two other important categories—history and cool science images.

Top History Post: HeLa Cells: A New Chapter in An Enduring Story. Published in August 2013, this post remains one of the blog’s greatest hits with readers. The post highlights science’s use of cancer cells taken in the 1950s from a young Black woman named Henrietta Lacks. These “HeLa” cells had an amazing property not seen before: they could be grown continuously in laboratory conditions. The “new chapter” featured in this post is an agreement with the Lacks family that gives researchers access to the HeLa genome data, while still protecting the family’s privacy and recognizing their enormous contribution to medical research. And the acknowledgments rightfully keep coming from those who know this remarkable story, which has been chronicled in both book and film. Recently, the U.S. Senate and House of Representatives passed the Henrietta Lacks Enhancing Cancer Research Act to honor her extraordinary life and examine access to government-funded cancer clinical trials for traditionally underrepresented groups.

Top Snapshots of Life: A Close-up of COVID-19 in Lung Cells. My blog posts come in several categories. One that you may have noticed is “Snapshots of Life,” which provides a showcase for cool images that appear in scientific journals and often dominate Science as Art contests. My blog has published dozens of these eye-catching images, representing a broad spectrum of the biomedical sciences. But the blog People’s Choice goes to a very recent addition that reveals exactly what happens to cells in the human airway when they are infected with the coronavirus responsible for COVID-19. This vivid image, published in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. This image squeezed in just ahead of another highly popular post from Steve Ramirez, Boston University, in 2019 that showed “What a Memory Looks Like.”

As we look ahead to 2021, I want to thank each of my blog’s readers for your views and comments over the last eight years. I love to hear from you, so keep on clicking! I’m confident that 2021 will generate a lot more amazing and bloggable science, including even more progress toward ending the COVID-19 pandemic that made our past year so very challenging.


What a Memory Looks Like

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Engram Image
Credit: Stephanie Grella, Ramirez Group, Boston University

Your brain has the capacity to store a lifetime of memories, covering everything from the name of your first pet to your latest computer password. But what does a memory actually look like? Thanks to some very cool neuroscience, you are looking at one.

The physical manifestation of a memory, or engram, consists of clusters of brain cells active when a specific memory was formed. Your brain’s hippocampus plays an important role in storing and retrieving these memories. In this cross-section of a mouse hippocampus, imaged by the lab of NIH-supported neuroscientist Steve Ramirez, at Boston University, cells belonging to an engram are green, while blue indicates those not involved in forming the memory.

When a memory is recalled, the cells within an engram reactivate and turn on, to varying degrees, other neural circuits (e.g., sight, sound, smell, emotions) that were active when that memory was recorded. It’s not clear how these brain-wide connections are made. But it appears that engrams are the gatekeepers that mediate memory.

The story of this research dates back several years, when Ramirez helped develop a system that made it possible to image engrams by tagging cells in the mouse brain with fluorescent dyes. Using an innovative technology developed by other researchers, called optogenetics, Ramirez’s team then discovered it could shine light onto a collection of hippocampal neurons storing a specific memory and reactivate the sensation associated with the memory [1].

Ramirez has since gone on to show that, at least in mice, optogenetics can be used to trick the brain into creating a false memory [2]. From this work, he has also come to the interesting and somewhat troubling conclusion that the most accurate memories appear to be the ones that are never recalled. The reason: the mammalian brain edits—and slightly changes—memories whenever they are accessed.

All of the above suggested to Ramirez that, given its tremendous plasticity, the brain may possess the power to downplay a traumatic memory or to boost a pleasant recollection. Toward that end, Ramirez’s team is now using its mouse system to explore ways of suppressing one engram while enhancing another [3].

For Ramirez, though, the ultimate goal is to develop brain-wide maps that chart all of the neural networks involved in recording, storing, and retrieving memories. He recently was awarded an NIH Director’s Transformative Research Award to begin the process. Such maps will be invaluable in determining how stress affects memory, as well as what goes wrong in dementia and other devastating memory disorders.

References:

[1] Optogenetic stimulation of a hippocampal engram activates fear memory recall. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S. Nature. 2012 Mar 22;484(7394):381-385.

[2] Creating a false memory in the hippocampus. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, Tonegawa S. Science. 2013 Jul 26;341(6144):387-391.

[3] Artificially Enhancing and Suppressing Hippocampus-Mediated Memories. Chen BK, Murawski NJ, Cincotta C, McKissick O, Finkelstein A, Hamidi AB, Merfeld E, Doucette E, Grella SL, Shpokayte M, Zaki Y, Fortin A, Ramirez S. Curr Biol. 2019 Jun 3;29(11):1885-1894.

Links:

The Ramirez Group (Boston University, MA)

Ramirez Project Information (Common Fund/NIH)

NIH Director’s Early Independence Award (Common Fund)

NIH Director’s Transformative Research Award (Common Fund)

NIH Support: Common Fund


Creative Minds: Seeing Memories in a New Light

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Steve Ramirez

Steve Ramirez/Joshua Sariñana

Whether it’s lacing up for a morning run, eating blueberry scones, or cheering on the New England Patriots, Steve Ramirez loves life and just about everything in it. As an undergraduate at Boston University, this joie de vivre actually made Ramirez anxious about choosing just one major. A serendipitous conversation helped him realize that all of the amazing man-made stuff in our world has a common source: the human brain.

So, Ramirez decided to pursue neuroscience and began exploring the nature of memory. Employing optogenetics (using light to control brain cells) in mice, he tagged specific neurons that housed fear-inducing memories, making the neurons light sensitive and amenable to being switched on at will.

In groundbreaking studies that earned him a spot in Forbes 2015 “30 Under 30” list, Ramirez showed that it’s possible to reactivate memories experimentally in a new context, recasting them in either a more negative or positive behavior-changing light [1–3]. Now, with support from a 2016 NIH Director’s Early Independence Award, Ramirez, who runs his own lab at Boston University, will explore whether activating good memories holds promise for alleviating chronic stress and psychiatric disease.


Mouse Study Finds Microbe Might Protect against Food Poisoning

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T mu in a mouse colon

Caption: Scanning electron microscopy image of T. mu in the mouse colon.
Credit: Aleksey Chudnovskiy and Miriam Merad, Icahn School of Medicine at Mount Sinai

Recently, we humans have started to pay a lot more attention to the legions of bacteria that live on and in our bodies because of research that’s shown us the many important roles they play in everything from how we efficiently metabolize food to how well we fend off disease. And, as it turns out, bacteria may not be the only interior bugs with the power to influence our biology positively—a new study suggests that an entirely different kingdom of primarily single-celled microbes, called protists, may be in on the act.

In a study published in the journal Cell, an NIH-funded research team reports that it has identified a new protozoan, called Tritrichomonas musculis (T. mu), living inside the gut of laboratory mice. That sounds bad—but actually this little wriggler was potentially providing a positive benefit to the mice. Not only did T. mu appear to boost the animals’ immune systems, it spared them from the severe intestinal infection that typically occurs after eating food contaminated with toxic Salmonella bacteria. While it’s not yet clear if protists exist that can produce similar beneficial effects in humans, there is evidence that a close relative of T. mu frequently resides in the intestines of people around the world.


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