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3D Neuroscience at the Speed of Life

Posted on by Dr. Francis Collins

This fluorescent worm makes for much more than a mesmerizing video. It showcases a significant technological leap forward in our ability to capture in real time the firing of individual neurons in a living, freely moving animal.

As this Caenorhabditis elegans worm undulates, 113 neurons throughout its brain and body (green/yellow spots) get brighter and darker as each neuron activates and deactivates. In fact, about halfway through the video, you can see streaks tracking the positions of individual neurons (blue/purple-colored lines) from one frame to the next. Until now, it would have been technologically impossible to capture this “speed of life” with such clarity.

With funding from the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, Elizabeth Hillman at Columbia University’s Zuckerman Institute, New York, has pioneered the pairing of a 3D live-imaging microscope with an ultra-fast camera. This pairing, showcased above, is a technique called Swept Confocally Aligned Planar Excitation (SCAPE) microscopy.

Since first demonstrating SCAPE in February 2015 [1], Hillman and her team have worked hard to improve, refine, and expand the approach. Recently, they used SCAPE 1.0 to image how proprioceptive neurons in fruit-fly larvae sense body position while crawling. Now, as described in Nature Methods, they introduce SCAPE “2.0,” with boosted resolution and a much faster camera—enabling 3D imaging at speeds hundreds of times faster than conventional microscopes [2]. To track a very wiggly worm, the researchers image their target 25 times a second!

As with the first-generation SCAPE, version 2.0 uses a scanning mirror to sweep a slanted sheet of light across a sample. This same mirror redirects light coming from the illuminated plane to focus onto a stationary high-speed camera. The approach lets SCAPE grab 3D imaging at very high speeds, while also causing very little photobleaching compared to conventional point-scanning microscopes, reducing sample damage that often occurs during time-lapse microscopy.

Like SCAPE 1.0, since only a single, stationary objective lens is used, the upgraded 2.0 system doesn’t need to hold, move, or disturb a sample during imaging. This flexibility enables scientists to use SCAPE in a wide range of experiments where they can present stimuli or probe an animal’s behavior—all while imaging how the underlying cells drive and depict those behaviors.

The SCAPE 2.0 paper shows the system’s biological versatility by also recording the beating heart of a zebrafish embryo at record-breaking speeds. In addition, SCAPE 2.0 can rapidly image large fixed, cleared, and expanded tissues such as the retina, brain, and spinal cord—enabling tracing of the shape and connectivity of cellular circuits. Hillman and her team are dedicated to exporting their technology; they provide guidance and a parts list for SCAPE 2.0 so that researchers can build their own version using inexpensive off-the-shelf parts.

Watching worms wriggling around may remind us of middle-school science class. But to neuroscientists, these images represent progress toward understanding the nervous system in action, literally at the speed of life!


[1] . Swept confocally-aligned planar excitation (SCAPE) microscopy for high speed volumetric imaging of behaving organisms. Bouchard MB, Voleti V, Mendes CS, Lacefield C, et al Nature Photonics. 2015;9(2):113-119.

[2] Real-time volumetric microscopy of in vivo dynamics and large-scale samples with SCAPE 2.0. Voleti V, Patel KB, Li W, Campos CP, et al. Nat Methods. 2019 Sept 27;16:1054–1062.


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)

NIH Support: National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute

Zooming In on Meiosis

Posted on by Dr. Francis Collins


Credit: Simone Köhler, Michal Wojcik, Ke Xu, and Abby Dernburg, University of California, Berkeley

Meiosis—the formation of egg and sperm cells—is a highly choreographed process that creates genetic diversity in all plants and animals, including humans, to make each of us unique. This kaleidoscopic image shows cells from a worm exchanging DNA during meiosis.

You can see a protein-based polymer tether (green) from what’s called the synaptonemal complex. The complex holds together partner chromosomes (magenta) to facilitate DNA exchange in nuclei (white). Moving from left to right are views of the molecular assembly that progressively zoom in on the DNA, revealing in exquisite detail (far right) the two paired partner chromosomes perfectly aligned. This is not just the familiar DNA double helix. This is a double helix made up of two double helices!

Rare Disease Mystery: Nodding Syndrome May Be Linked to Parasitic Worm

Posted on by Dr. Francis Collins

Rural Uganda village gathering

Caption: Village in the East Africa nation of Uganda
Credit: Centers for Disease Control and Prevention

In the early 1960s, reports began to surface that some children living in remote villages in East Africa were suffering mysterious episodes of “head nodding.” The condition, now named nodding syndrome, is recognized as a rare and devastating form of epilepsy. There were hints that the syndrome might be caused by a parasitic worm called Onchocerca volvulus, which is transmitted through the bites of blackflies. But no one had been able to tie the parasitic infection directly to the nodding heads.

Now, NIH researchers and their international colleagues think they’ve found the missing link. The human immune system turns out to be a central player. After analyzing blood and cerebrospinal fluid of kids with nodding syndrome, they detected a particular antibody at unusually high levels [1]. Further studies suggest the immune system ramps up production of that antibody to fight off the parasite. The trouble is those antibodies also react against a protein in healthy brain tissue, apparently leading to progressive cognitive dysfunction, neurological deterioration, head nodding, and potentially life-threatening seizures.

The findings, published in Science Translational Medicine, have important implications for the treatment and prevention of not only nodding syndrome, but perhaps other autoimmune-related forms of epilepsy. As people in the United States and around the globe today observe the 10th anniversary of international Rare Disease Day, this work provides yet another example of how rare disease research can shed light on more common diseases and fundamental aspects of human biology.

Creative Minds: The Worm Tissue-ome Teaches Developmental Biology for Us All

Posted on by Dr. Francis Collins

C. elegans
Caption: An adult Caenorhabditis elegans, 5 days
Credit: Coleen Murphy, Princeton University, Princeton, NJ

In the nearly 40 years since Nobel Prize-winning scientist Sydney Brenner proposed using a tiny, transparent soil worm called Caenorhabditis elegans as a model organism for biomedical research, C. elegans has become one of the most-studied organisms on the planet. Researchers have determined that C. elegans has exactly 959 cells, 302 of which are neurons. They have sequenced and annotated its genome, developed an impressive array of tools to study its DNA, and characterized the development of many of its tissues.

But what researchers still don’t know is exactly how all of these parts work together to coordinate this little worm’s response to changes in nutrition, environment, health status, and even the aging process. To learn more, 2015 NIH Director’s Pioneer Award winner Coleen Murphy of Princeton University, Princeton, NJ, has set out to analyze which genes are active, or transcribed, in each of the major tissues of adult C. elegans, building the framework for what’s been dubbed the C. elegans “tissue-ome.”

Snapshots of Life: A Kaleidoscope of Worms

Posted on by Dr. Francis Collins

C. elegans

Credit: Adam Brown and David Biron, University of Chicago

What might appear to be a view inside an unusual kaleidoscope is actually a laboratory plate full of ravenous roundworms (Caenorhabditis elegans) as seen through a microscope. Tens of thousands of worms (black), each about 1 millimeter in length at adulthood, are grazing on a field of bacteria beneath them. The yellow is a jelly-like growth medium called agar that feeds the bacteria, and the orange along the borders was added to enhance the sunburst effect.

The photo was snapped and stylized by NIH training grantee Adam Brown, a fourth-year Ph.D. student in the lab of David Biron at the University of Chicago. Brown uses C. elegans to study the neurotransmitter serotonin, a popular drug target in people receiving treatment for depression and other psychiatric disorders. This tiny, soil-dwelling worm is a go-to model organism for neuroscientists because of its relative simplicity, short life spans, genetic malleability, and complete cell-fate map. By manipulating the different components of the serotonin-signaling system in C. elegans, Brown and his colleagues hope to better understand the most basic circuitry in the central nervous system that underlies decision making, in this case choosing to feed or forage.

Snapshots of Life: NIH’s BioArt Winners

Posted on by Dr. Francis Collins

Brick wall adorned with poster-sized prints of winning photos

Credit: FASEB

If you follow my blog, you know that I like to feature spectacular images that scientists have created during the course of their research. These images are rarely viewed outside the lab, but some are so worthy of artistic merit and brimming with educational value that they deserve a wider audience. That’s one reason why the Federation of American Societies for Experimental Biology (FASEB) launched its BioArt contest. Of the 12 winners in 2013, I’m proud to report that 11 received support from NIH. In fact, I’m so proud that I plan to showcase their work in an occasional series entitled “Snapshots of Life.” Continue reading to see the first installment—enjoy!