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NIH at 80: Sharing a Timeless Message from President Roosevelt

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This Saturday, October 31, marks an important milestone in American public health: the 80th anniversary of President Franklin Delano Roosevelt’s dedication of the campus of the National Institutes of Health (NIH) in Bethesda, MD. The President’s stirring speech, delivered from the steps of NIH’s brand-new Administration Building (now called Building 1), was much more than a ribbon-cutting ceremony. It gave voice to NIH’s commitment to using the power of science “to do infinitely more” for the health of all people with “no distinctions of race, of creed, or of color.”

“We cannot be a strong nation unless we are a healthy nation. And so, we must recruit not only men and materials, but also knowledge and science in the service of national strength,” Roosevelt told the crowd of about 3,000. To get a sense of what it was like to be there on that historic day, I encourage you to check out the archival video footage above from the National Archives and Records Administration (NARA).

These words from our 32nd President are especially worth revisiting for their enduring wisdom during a time of national crisis. In October 1940, with World War II raging overseas, the United States faced the prospect of defending its shores and territories from foreign forces. Yet, at the same time as he was bolstering U.S. military capacity, Roosevelt emphasized that it was also essential to use biomedical research to shore up our nation’s defenses against the threats of infectious disease. In a particularly prescient section of the speech, he said: “Now that we are less than a day by plane from the jungle-type yellow fever of South America, less than two days from the sleeping sickness of equatorial Africa, less than three days from cholera and bubonic plague, the ramparts we watch must be civilian in addition to military.”

Today, in the midst of another national crisis—the COVID-19 pandemic—a similar vision is inspiring the work of NIH. With the aim of defending the health of all populations, we are supporting science to understand the novel coronavirus that causes COVID-19 and to develop tests, treatments, and vaccines for this disease that has already killed more than 225,000 Americans and infected more than 8.6 million.

As part of the dedication ceremony, Roosevelt thanked the Luke and Helen Wilson family for donating their 70-acre estate, “Tree Tops,” to serve as a new home for NIH. (Visitors to Wilson Hall in Building 1 will see portraits of the Wilsons.) Founded in 1887, NIH had previously been housed in a small lab on Staten Island, and then in two cramped lab buildings in downtown Washington, D.C. The move to Bethesda, with NIH’s first six buildings already dotting the landscape as Roosevelt spoke, gave the small agency room to evolve into what today is the world’s largest supporter of biomedical research.

Yet, as FDR gazed out over our fledging campus on that autumn day so long ago, he knew that NIH’s true mission would extend far beyond simply conducting science to providing much-needed hope to humans around the world. As he put it in his closing remarks: “I voice for America and for the stricken world, our hopes, our prayers, our faith, in the power of man’s humanity to man.”

On the 80th anniversary of NIH’s move to Bethesda, I could not agree more. Our science—and our humanity—will get us through this pandemic and show the path forward to brighter days ahead.

Links:

Who We Are: History (NIH)

Office of NIH History and Stetten Museum (NIH)

70 Acres of Science” (Office of NIH History)

Coronavirus (COVID-19) (NIH)


The Amazing Brain: Shining a Spotlight on Individual Neurons

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A major aim of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is to develop new technologies that allow us to look at the brain in many different ways on many different scales. So, I’m especially pleased to highlight this winner of the initiative’s recent “Show Us Your Brain!” contest.

Here you get a close-up look at pyramidal neurons located in the hippocampus, a region of the mammalian brain involved in memory. While this tiny sample of mouse brain is densely packed with many pyramidal neurons, researchers used new ExLLSM technology to zero in on just three. This super-resolution, 3D view reveals the intricacies of each cell’s structure and branching patterns.

The group that created this award-winning visual includes the labs of X. William Yang at the University of California, Los Angeles, and Kwanghun Chung at the Massachusetts Institute of Technology, Cambridge. Chung’s team also produced another quite different “Show Us Your Brain!” winner, a colorful video featuring hundreds of neural cells and connections in a part of the brain essential to movement.

Pyramidal neurons in the hippocampus come in many different varieties. Some important differences in their functional roles may be related to differences in their physical shapes, in ways that aren’t yet well understood. So, BRAIN-supported researchers are now applying a variety of new tools and approaches in a more detailed effort to identify and characterize these neurons and their subtypes.

The video featured here took advantage of Chung’s new method for preserving brain tissue samples [1]. Another secret to its powerful imagery was a novel suite of mouse models developed in the Yang lab. With some sophisticated genetics, these models make it possible to label, at random, just 1 to 5 percent of a given neuronal cell type, illuminating their full morphology in the brain [2]. The result was this unprecedented view of three pyramidal neurons in exquisite 3D detail.

Ultimately, the goal of these and other BRAIN Initiative researchers is to produce a dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. I look forward to their continued progress, which promises to revolutionize our understanding of how the human brain functions in both health and disease.

References:

[1] Protection of tissue physicochemical properties using polyfunctional crosslinkers. Park YG, Sohn CH, Chen R, McCue M, Yun DH, Drummond GT, Ku T, Evans NB, Oak HC, Trieu W, Choi H, Jin X, Lilascharoen V, Wang J, Truttmann MC, Qi HW, Ploegh HL, Golub TR, Chen SC, Frosch MP, Kulik HJ, Lim BK, Chung K. Nat Biotechnol. 2018 Dec 17.

[2] Genetically-directed Sparse Neuronal Labeling in BAC Transgenic Mice through Mononucleotide Repeat Frameshift. Lu XH, Yang XW. Sci Rep. 2017 Mar 8;7:43915.

Links:

Chung Lab (Massachusetts Institute of Technology, Cambridge)

Yang Lab (University of California, Los Angeles)

Show Us Your Brain! (BRAIN Initiative/NIH)

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

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


Watch Flowers Spring to Life

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Spring has sprung! The famous Washington cherry blossoms have come and gone, and the tulips and azaleas are in full bloom. In this mesmerizing video, you’ll get a glimpse of the early steps in how some spring flowers bloom.

Floating into view are baby flowers, their cells outlined (red), at the tip of the stem of the mustard plant Arabidopsis thaliana. Stem cells that contain the gene STM (green) huddle in the center of this fast-growing region of the plant stem—these stem cells will later make all of the flower parts.

As the video pans out, slightly older flowers come into view. These contain organs called sepals (red, bumpy outer regions) that will grow into leafy support structures for the flower’s petals.

Movie credits go to Nathanaёl Prunet, an assistant professor at the University of California, Los Angeles, who shot this video while working in the NIH-supported lab of Elliot Meyerowitz at the California Institute of Technology, Pasadena. Prunet used confocal microscopy to display the different ages and stages of the developing flowers, generating a 3D data set of images. He then used software to produce a bird’s-eye view of those images and turned it into a cool movie. The video was one of the winners in the Federation of American Societies for Experimental Biology’s 2018 BioArt competition.

Beyond being cool, this video shows how a single gene, STM, plays a starring role in plant development. This gene acts like a molecular fountain of youth, keeping cells ever-young until it’s time to grow up and commit to making flowers and other plant parts.

Like humans, most plants begin life as a fertilized cell that divides over and over—first into a multi-cell embryo and then into mature parts, or organs. Because of its ease of use and low cost, Arabidopsis is a favorite model for scientists to learn the basic principles driving tissue growth and regrowth for humans as well as the beautiful plants outside your window. Happy Spring!

Links:

Meyerowitz Lab (California Institute of Technology, Pasadena)

Prunet Lab (University of California, Los Angeles)

The Arabidosis Information Resource (Phoenix Bioinformatics, Fremont, CA)

BioArt Scientific Image and Video Competition (Federation of American Societies for Experimental Biology, Bethesda, MD)

NIH Support: National Institute of General Medical Sciences


Finding Beauty in the Nervous System of a Fruit Fly Larva

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Wow! Click on the video. If you’ve ever wondered where those pesky flies in your fruit bowl come from, you’re looking at it right now. It’s a fruit fly larva. And this 3D movie offers never-before-seen details into proprioception—the brain’s sixth sense of knowing the body’s location relative to nearby objects or, in this case, fruit.

This live-action video highlights the movement of the young fly’s proprioceptive nerve cells. They send signals to the fly brain that are essential for tracking the body’s position in space and coordinating movement. The colors indicate the depth of the nerve cells inside the body, showing those at the surface (orange) and those further within (blue).

Such movies make it possible, for the first time, to record precisely how every one of these sensory cells is arranged within the body. They also provide a unique window into how body positions are dynamically encoded in these cells, as a segmented larva inches along in search of food.

The video was created using a form of confocal microscopy called Swept Confocally Aligned Planar Excitation, or SCAPE. It captures 3D images by sweeping a sheet of laser light back and forth across a living sample. Even better, it does this while the microscope remains completely stationary—no need for a researcher to move any lenses up or down, or hold a live sample still.

Most impressively, with this new high-speed technology, developed with support from the NIH’s BRAIN Initiative, researchers are now able to capture videos like the one seen above in record time, with each whole volume recorded in under 1/10th of a second! That’s hundreds of times faster than with a conventional microscope, which scans objects point by point.

As reported in Current Biology, the team, led by Elizabeth Hillman and Wesley Grueber, Columbia University, New York, didn’t stop at characterizing the structural details and physical movements of nerve cells involved in proprioception in a crawling larva. In another set of imaging experiments, they went a step further, capturing faint flashes of green in individual labeled nerve cells each time they fired. (You have to look very closely to see them.) With each wave of motion, proprioceptive nerve cells light up in sequence, demonstrating precisely when they are sending signals to the animal’s brain.

From such videos, the researchers have generated a huge amount of data on the position and activity of each proprioceptive nerve cell. The data show that the specific position of each cell makes it uniquely sensitive to changes in position of particular segments of a larva’s body. While most of the proprioceptive nerve cells fired when their respective body segment contracted, others were attuned to fire when a larval segment stretched.

Taken together, the data show that proprioceptive nerve cells provide the brain with a detailed sequence of signals, reflecting each part of a young fly’s undulating body. It’s clear that every proprioceptive neuron has a unique role to play in the process. The researchers now will create similar movies capturing neurons in the fly’s central nervous system.

A holy grail of the BRAIN Initiative is to capture the brain in action. With these advances in imaging larval flies, researchers are getting ever closer to understanding the coordinated activities of an organism’s complete nervous system—though this one is a lot simpler than ours! And perhaps this movie—and the anticipation of the sequels to come—may even inspire a newfound appreciation for those pesky flies that sometimes hover nearby.

Reference:

[1] Characterization of Proprioceptive System Dynamics in Behaving Drosophila Larvae Using High-Speed Volumetric Microscopy. Vaadia RD, Li W, Voleti V, Singhania A, Hillman EMC, Grueber WB. Curr Biol. 2019 Mar 18;29(6):935-944.e4.

Links:

Using Research Organisms to Study Health and Disease (National Institute of General Medical Sciences/NIH)

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

Hillman Lab (Columbia University, New York)

Grueber Lab (Columbia University, New York)

NIH Support: National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development


World’s Smallest Tic-Tac-Toe Game Built from DNA

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Check out the world’s smallest board game, a nanoscale match of tic-tac-toe being played out in a test tube with X’s and O’s made of DNA. But the innovative approach you see demonstrated in this video is much more than fun and games. Ultimately, researchers hope to use this technology to build tiny DNA machines for a wide variety of biomedical applications.

Here’s how it works. By combining two relatively recent technologies, an NIH-funded team led by Lulu Qian, California Institute of Technology, Pasadena, CA, created a “swapping mechanism” that programs dynamic interactions between complex DNA nanostructures [1]. The approach takes advantage of DNA’s modular structure, along with its tendency to self-assemble, based on the ability of the four letters of DNA’s chemical alphabet to pair up in an orderly fashion, A to T and C to G.

To make each of the X or O tiles in this game (displayed here in an animated cartoon version), researchers started with a single, long strand of DNA and many much shorter strands, called staples. When the sequence of DNA letters in each of those components is arranged just right, the longer strand will fold up into the desired 2D or 3D shape. This technique is called DNA origami because of its similarity to the ancient art of Japanese paper folding.

In the early days of DNA origami, researchers showed the technique could be used to produce miniature 2D images, such as a smiley face [2]. Last year, the Caltech group got more sophisticated—using DNA origami to produce the world’s smallest reproduction of the Mona Lisa [3].

In the latest work, published in Nature Communications, Qian, Philip Petersen and Grigory Tikhomirov first mixed up a solution of nine blank DNA origami tiles in a test tube. Those DNA tiles assembled themselves into a tic-tac-toe grid. Next, two players took turns adding one of nine X or O DNA tiles into the solution. Each of the game pieces was programmed precisely to swap out only one of the tile positions on the original, blank grid, based on the DNA sequences positioned along its edges.

When the first match was over, player X had won! More importantly for future biomedical applications, the original, blank grid had been fully reconfigured into a new structure, built of all-new, DNA-constructed components. That achievement shows not only can researchers use DNA to build miniature objects, they can also use DNA to repair or reconfigure such objects.

Of course, the ultimate aim of this research isn’t to build games or reproduce famous works of art. Qian wants to see her DNA techniques used to produce tiny automated machines, capable of performing basic tasks on a molecular scale. In fact, her team already has used a similar approach to build nano-sized DNA robots, programmed to sort molecules in much the same way that a person might sort laundry [4]. Such robots may prove useful in miniaturized approaches to drug discovery, development, manufacture, and/or delivery.

Another goal of the Caltech team is to demonstrate to the scientific community what’s possible with this leading-edge technology, in hopes that other researchers will pick up their innovative tools for their own applications. That would be a win-win for us all.

References:

[1] Information-based autonomous reconfiguration in systems of DNA nanostructures. Petersen P, Tikhomirov G, Qian L. Nat Commun. 2018 Dec 18;9(1):5362

[2] Folding DNA to create nanoscale shapes and patterns. Rothemund PW. Nature. 2006 Mar 16;440(7082):297-302.

[3] Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns. Tikhomirov G, Petersen P, Qian L. Nature. 2017 Dec 6;552(7683):67-71.

[4] A cargo-sorting DNA robot. Thubagere AJ, Li W, Johnson RF, Chen Z, Doroudi S, Lee YL, Izatt G, Wittman S, Srinivas N, Woods D, Winfree E, Qian L. Science. 2017 Sep 15;357(6356).

Links:

Paul Rothemund—DNA Origami: Folded DNA as a Building Material for Molecular Devices (Cal Tech, Pasadena)

The World’s Smallest Mona Lisa (Caltech)

Qian Lab (Caltech, Pasadena, CA)

NIH Support: National Institute of General Medical Sciences


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