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Singing for the Fences

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Credit: NIH

I’ve sung thousands of songs in my life, mostly in the forgiving company of family and friends. But, until a few years ago, I’d never dreamed that I would have the opportunity to do a solo performance of the Star-Spangled Banner in a major league ballpark.

When I first learned that the Washington Nationals had selected me to sing the national anthem before a home game with the New York Mets on May 24, 2016, I was thrilled. But then another response emerged: yes, that would be called fear. Not only would I be singing before my biggest audience ever, I would be taking on a song that’s extremely challenging for even the most accomplished performer.

The musician in me was particularly concerned about landing the anthem’s tricky high F note on “land of the free” without screeching or going flat. So, I tracked down a voice teacher who gave me a crash course about how to breathe properly, how to project, how to stay on pitch on a high note, and how to hit the national anthem out of the park. She suggested that a good way to train is to sing the entire song with each syllable replaced by “meow.” It sounds ridiculous, but it helped—try it sometime. And then I practiced, practiced, practiced. I think the preparation paid off, but watch the video to decide for yourself!

Three years later, the scientist in me remains fascinated by what goes on in the human brain when we listen to or perform music. The NIH has even partnered with the John F. Kennedy Center for the Performing Arts to launch the Sound Health initiative to explore the role of music in health. A great many questions remain to be answered. For example, what is it that makes us enjoy singers who stay on pitch and cringe when we hear someone go sharp or flat? Why do some intervals sound pleasant and others sound grating? And, to push that line of inquiry even further, why do we tune into the pitch of people’s voices when they are speaking to help figure out if they are happy, sad, angry, and so on?

To understand more about the neuroscience of pitch, a research team, led by Bevil Conway of NIH’s National Eye Institute, used functional MRI imaging to study activity in the region of the brain involved in processing sound (the auditory cortex), both in humans and in our evolutionary relative, the macaque monkey [1]. For purposes of the study, published recently in Nature Neuroscience, pitch was defined as the harmonic sounds that we hear when listening to music.

For humans and macaques, their auditory cortices lit up comparably in response to low- and high-frequency sound. But only humans responded selectively to harmonic tones, while the macaques reacted to toneless, white noise sounds spanning the same frequency range. Based on what they found in both humans and monkeys, the researchers suspect that macaques experience music and other sounds differently than humans. They also go on to suggest that the perception of pitch must have provided some kind of evolutionary advantage for our ancestors, and has therefore apparently shaped the basic organization of the human brain.

But enough about science and back to the ballpark! In front of 33,009 pitch-sensitive Homo sapiens, I managed to sing our national anthem without audible groaning from the crowd. What an honor it was! I pass along this memory to encourage each of you to test your own pitch this Independence Day. Let’s all celebrate the birth of our great nation. Have a happy Fourth!

Reference:

[1] Divergence in the functional organization of human and macaque auditory cortex revealed by fMRI responses to harmonic tones. Norman-Haignere SV, Kanwisher N, McDermott JH, Conway BR. Nat Neurosci. 2019 Jun 10. [Epub ahead of print]

Links:

Our brains appear uniquely tuned for musical pitch (National Institute of Neurological Diseases and Stroke news release)

Sound Health: An NIH-Kennedy Center Partnership (NIH)

Bevil Conway (National Eye Institute/NIH)

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


Progress Toward 3D Printed Human Organs

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There’s considerable excitement that 3D printing technology might one day allow scientists to produce fully functional replacement organs from one’s own cells. While there’s still a lot to learn, this video shows just some of the amazing progress that’s now being made.

The video comes from a bioengineering team at Rice University, Houston, that has learned to bioprint the small air sacs in the lungs. When hooked up to a machine that pulsed air in and out of the air sacs, the rhythmic movement helped to mix red blood cells traveling through an associated blood vessel network. Those red cells also took up oxygen in much the way that blood vessels do when surrounding the hundreds of millions of air sacs in our lungs.

As mentioned in the video, one of the biggest technical hurdles in growing fully functional replacement tissues and organs is to find a way to feed the growing tissues with a blood supply and to remove waste products. In this study recently published in Science [1], the NIH-supported team cleared this hurdle by creating an open-source bioprinting technology they call SLATE, which is short for “stereo-lithography apparatus for tissue engineering.”

The SLATE system “grows” soft hydrogel scaffolds one layer at a time. Each layer is printed using a liquid pre-hydrogel solution that solidifies when exposed to blue light. By also projecting light into the hydrogel as a pixelated 3D shape, it’s possible to print complex 3D structures within minutes.

When the researchers first started, their printouts lacked the high resolution, submillimeter-scale channels needed to generate intricate vascular networks. In other manufacturing arenas, light-absorbing chemicals have helped control the conversion from liquid to solid in a very fine polymer layer. But these industrial light-absorbing chemicals are highly toxic and therefore unsuitable for scaffolds that grow living tissues and organs.

The researchers, including Bagrat Grigoryan, Jordan Miller, and Kelly Stevens, wondered whether they could swap out those noxious ingredients with synthetic and natural food dyes widely used in the food industry. These dyes include curcumin, anthocyanin, and tartrazine (yellow dye #5). Their studies showed that those fully biocompatible dyes worked as effective light absorbers, allowing the scientists to recreate the complex architectures of human vasculature. Importantly, the living cells survived within the soft scaffold!

These models are already yielding intriguing new insights into the vascular structures found within our organs and how those architectures may influence function in ways that hadn’t been well understood. In the near term, tissues and organs grown on such scaffolds might also find use as sophisticated, 3D tissue “chips,” with potential for use in studies to predict whether drugs will be safe in humans.

In the long term, this technology may allow production of replacement organs from those needing them. More than 100,000 men, women, and children are on the national transplant waiting list in the United States alone and 20 people die each day waiting for a transplant [2]. Ultimately, with the aid of bioprinting advances like this one, perhaps one day we’ll have a ready supply of perfectly matched and fully functional organs.

References:

[1] Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Grigoryan B, Paulsen SJ, Corbett DC, Sazer DW, Fortin CL, Zaita AJ, Greenfield PT, Calafat NJ, Gounley JP, Ta AH, Johansson F, Randles A, Rosenkrantz JE, Louis-Rosenberg JD, Galie PA, Stevens KR, Miller JS. Science. 2019 May 3;364(6439):458-464.

[2] Organ Donor Statistics, Health Resources & Services Administration, October 2018.

Links:

Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Miller Lab (Rice University, Houston)

NIH Support: National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of General Medical Sciences; Common Fund


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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