Category: Cells

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Restoring the Function of an Immune Receptor Involved in Crohn’s Disease

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Gut bacteria
Receptor proteins bind to bacterial cell wall fragments, initiating an immune response to remove bad gut bacteria. Credit: S. Melanie Lee, Caltech; Zbigniew Mikulski and Klaus Ley, La Jolla Institute for Allergy and Immunology.

Our bodies depend on a set of immune receptors to remove harmful bacteria and control the growth of helpful bacteria in our guts. Genetic changes that alter the function of the receptors can have an adverse effect and result in chronic inflammatory diseases like Crohn’s disease. Catherine Leimkuhler Grimes and Vishnu Mohanan of the University of Delaware researched a Crohn’s-associated immune receptor, NOD2, to figure out how it can lose the ability to respond properly to bacteria. In the process, they identified the involvement of a protective protein called HSP70. Increasing HSP70 levels in kidney, colon and white blood cells appeared to restore NOD2 function. This work represents a first step toward developing drugs to treat Crohn’s disease.

This work was funded in part by an Institutional Development Award (IDeA) Network of Biomedical Research Excellence (INBRE) grant.

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Anesthesia and Brain Cells: A Temporary Disruption?

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Hippocampal neuron in culture.
Hippocampal neuron in culture. Dendrites are green, dendritic spines are red, and DNA in cell’s nucleus is blue. Credit: Shelley Halpain, University of California, San Diego.

Anesthetic drugs are vital to modern medicine, allowing patients to undergo even the longest and most invasive surgeries without consciousness or pain. Unfortunately, studies have raised the concern that exposing patients, particularly children and the elderly, to some anesthetics may increase risk of long-term cognitive and behavioral issues.

A scientific team led by Hugh Hemmings Exit icon of Weill Cornell Medical College and Shelley Halpain Exit icon of the University of California, San Diego, examined the effects of anesthesia on neurons isolated from juvenile rats. Given at doses and durations frequently used during surgery, the commonly administered general anesthetic isoflurane did in fact reduce the number and size of important structures within neurons called dendritic spines. Dendritic spines help pass information from neuron to neuron, and disruption of these structures can be associated with dysfunction in thinking and behavior.

Promisingly, the shrinkage observed by the researchers appeared to be temporary: After the researchers washed the anesthetic out of the cell cultures, the dendritic spines grew back. But because neurons in culture do not reproduce all aspects of intact neuronal networks, the scientists explain that the findings should be verified in more complex models. Other molecular mechanisms may also potentially contribute to late effects of anesthesia exposure.

This work also was funded by NIH’s National Institute of Mental Health.

Learn more:
University of California, San Diego News Release Exit icon
Understanding Anesthesia from Inside Life Science

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Meet Janet Iwasa

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Janet Iwasa
Credit: Janet Iwasa
Janet Iwasa
Fields: Cell biology and molecular animation
Works at: University of Utah
Raised in: Indiana and Maryland
Studied at: University of California, San Francisco, and Harvard Medical School
When not in the lab she’s: Keeping up with her two preschool-aged sons
Something she’s proud of that she’ll never try again: Baking a multi-tiered wedding cake, complete with sugar flowers, for a friend’s wedding.

Janet Iwasa wouldn’t have described herself as an artistic child. She didn’t carry around a sketch pad, pencils or paintbrushes. But she remembers accompanying her father, a scientist at the National Institutes of Health, to his lab on the weekends. She’d spend hours doodling in a drawing program on his old Macintosh computer while he worked on experiments.

“I always remember wanting to be a scientist, and that’s probably highly inspired by my dad,” says Iwasa. Her early affinity for art and technology set her on an unusual career path to become a molecular animator. A typical work day now finds her adapting computer programs originally designed to bring characters like Buzz Lightyear to life to help researchers probe complicated, dynamic interactions within cells.

Iwasa’s interest in animation was sparked when she was a graduate student in cell biology, studying a protein called actin, which helps cells to move and change shape. At the time, the only visual representations she had of actin networks were flat, two-dimensional drawings on paper. When she saw an animation of the dynamic movement of a molecule called kinesin, she thought, “Why are we relying on oversimplified, static illustrations [of molecules], when we can be doing something like this video?”

Within a year, she was taking an animation class at a local college. She quickly realized that she would need more intensive instruction to be able to animate complex biological processes. A few summers later, she flew to Hollywood for a 3-month training program in industry-standard animation technology.

The oldest student in that course—and the only woman—Iwasa immediately began thinking about how to adapt a standard animator’s toolkit to illustrate the inner life of cells. A technique used to create the effect of human hair blowing in the wind could also show the movement of an RNA molecule. A chunk of computer code used to make the facets of a soccer ball fall apart and come back together in a different order could be adapted to model virus assembly and disassembly.

Her Findings

Following her training, Iwasa spent 2 years as a National Science Foundation Discovery Corps fellow, producing the Exploring Life’s Origins exhibit with the Boston Museum of Science and the Szostak Lab at Massachusetts General Hospital/Harvard Medical School. As part of the multi-media exhibit, she created animations to illustrate how the simplest living organisms may have evolved on early Earth.

Since then, Iwasa has helped researchers model such complex actions as how cells ingest materials, how proteins are transported across a cell membrane, and how the motor protein dynein helps cells divide.

Screenshot from the video that shows how a protein called clathrin forms a cage-like container that cells use to engulf and ingest materials
Iwasa developed this video to show how a protein called clathrin forms a cage-like container that cells use to engulf and ingest materials.

Iwasa calls her animations “visual hypotheses”: The end results may be beautiful, but the process of animation itself is what encapsulates, clarifies and communicates the science.

“It’s really building the animated model that brings insights,” she says. “When you’re creating an animation, you’re really grappling with a lot of issues that don’t necessarily come up by any other means. In some cases, it might raise more questions, and make people go back and do some more experiments when they realize there might be something missing” in their theory of how a molecular process works.

Now she’s working with an NIH-funded research team at the University of Utah to develop a detailed animation of how HIV enters and exits human immune cells.

Abbreviated CHEETAH, the full name of the group is the Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV.

“In the HIV life cycle, there are a number of events that aren’t really well understood, and people have different ideas of how things happen,” says Iwasa. She plans to animate the stages of viral infection in ways that reflect different proposals for how the process works, to give researchers a new way to visualize, communicate—and potentially harmonize—their hypotheses.

The full set of Iwasa’s HIV-related animations will be available online as they are completed, at https://scienceofhiv.org, with the first set launching in the fall of 2014.

Learn more:
Janet Iwasa’s TED Talk: How animations can help scientists test a hypothesis
Janet Iwasa’s 3D model of an HIV particle was a winner in the 2014 BioArt contest sponsored by Federation of American Societies for Experimental Biology
NIH Director’s blog post about Iwasa and her HIV video animation

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The “Virtuous Cycle” of Technology and Science

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A scientist looking through a microscope. Credit: Stock image.
Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Credit: Stock image.

Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Its central role is particularly clear from this month’s posts.

Some show how different tools led to basic discoveries with important health applications. For instance, a supercomputer unlocked the secrets of a drug-making enzyme, a software tool identified disease-causing variations among family members and high-powered microscopy revealed a mechanism allowing microtubules—and a cancer drug that targets them—to work.

Another theme featured in several posts is novel uses for established technologies. The scientists behind the cool image put a new spin on a long-standing imaging technology to gain surprising insights into how some brain cells dispose of old parts. Similarly, the finding related to sepsis demonstrates yet another application of a standard lab technique called polymerase chain reaction: assessing the immune state of people with this serious medical condition.

“We need tools to answer questions,” says NIGMS’ Doug Sheeley, who oversees biomedical technology research resource grants. “When we find the answers, we ask new questions that then require new or improved tools. It’s a virtuous cycle that keeps science moving forward.”

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Cool Image: Outsourcing Cellular Housekeeping

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Mouse optic nerve and retina. Credit: Keunyoung Kim, Thomas Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research, UC San Diego.

This image shows the mouse optic nerve and retina. Credit: Keunyoung Kim, Thomas Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research Exit icon, UC San Diego.

In this image, the optic nerve (left) leaves the back of the retina (right). Where the retina meets the optic nerve, visual information begins its journey from the eye to the brain. Taking a closer look, axons (purple), which carry electrical and chemical messages, meet astrocytes (yellow), a type of brain cell. Recent research has found a new and surprising role for these astrocytes.

Biologists have long thought that all cells, including neurons, degrade and reuse pieces of their own mitochondria, the little powerhouses that provide energy to cells. Using cutting-edge imaging technology, researchers led by Mark Ellisman of the University of California, San Diego, and Nicholas Marsh-Armstrong of Johns Hopkins University have caught neurons in the mouse optic nerve in the act of passing some of their worn out mitochondria to neighboring astrocytes, which then did the dirty work of recycling.

The researchers also showed that neurons in other regions of the brain appear to outsource mitochondrial breakdown to astrocytes as well. They suggest that it will be important to confirm that this process occurs in other parts of the brain and to determine how possible defects in the outsourcing may contribute to or underlie neuronal dysfunction or neurodegenerative diseases.

This work also was funded by NIH’s National Eye Institute and National Institute on Drug Abuse.

Learn more:
University of California, San Diego News Release Exit icon and Blog Posting Exit icon
How Cells Take Out the Trash Article from Inside Life Science

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Cool Video: How a Microtubule Builds and Deconstructs

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A microtubule, part of the cell’s skeleton, builds and deconstructs. Credit: Eva Nogales lab, University of California, Berkeley.

In this animation, tubulin proteins snap into place like Lego blocks to build a microtubule, part of the cell’s skeleton. When construction ends, this long hollow cylinder falls to pieces from its top end. The breakdown is critical for many basic biological processes, including cell division, when rapidly shortening microtubules pull chromosomes into each daughter cell.

Until recently, scientists didn’t know exactly what drove microtubules to fall apart. A research team led by Eva Nogales of the Lawrence Berkeley National Laboratory and the University of California, Berkeley, now has an explanation.

Using high-powered microscopy, the scientists peered into the structure of a microtubule and found how a chemical reaction puts the stacking tubulin proteins under intense strain. The only thing keeping the proteins from springing apart is the pressure from the addition of more tubulin. So when assembly stops, the microtubule deconstructs.

The team also learned that Taxol, a common cancer drug, relieves this tension and allows microtubules to remain intact indefinitely. With microtubules frozen in place, a cancer cell cannot divide and eventually dies.

Because of this research, scientists now better understand both the success behind a common cancer drug and the molecular basis underlying the workings of microtubules.

Learn more:
University of California, Berkeley News Release Exit icon
Nogales Lab

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Revealing a Key Player in Cancer Metastasis

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Invadopodia
A newly designed fluorescent biosensor shows where Rac1, a molecule involved in cancer metastasis, is active in this cell. Warmer colors show greater Rac1 activity. Credit: Yasmin Moshfegh, Albert Einstein College of Medicine.

Most of the more than half-a-million deaths caused by cancer each year in the United States result not from the original tumor but from the spread of cancer to new parts of the body, or metastasis. Cancer cells travel from a primary tumor using invadopodia, foot-like protrusions that break through surrounding connective tissue. Invadopodia are driven by protein filaments that repeatedly grow and disassemble. Exactly what guides this cycle was unclear, but scientists suspected a molecule called Rac1 might be involved. A new tool now sheds light on the details.

Researchers led by Louis Hodgson of Albert Einstein College of Medicine developed a fluorescent biosensor that glows wherever Rac1 is active in a cell, and they used it to study highly invasive breast cancer cells taken from rodents and humans. The scientists observed invadopodia form when Rac1 activity was low and disappear when it was high. They then confirmed their findings when they shut down the gene that encodes Rac1 and saw the invadopodia remain intact indefinitely.

This discovery suggests that targeting Rac1 activity with drugs could stop the spread of cancer cells. But a major hurdle remains: Healthy cells, including those that make up our immune system, also rely on the molecule for normal activity. Researchers must find a way to turn off Rac1 in cancer cells without disrupting its function in the rest of the body.

This work also was funded by NIH’s National Cancer Institute.

Learn more:
Albert Einstein College of Medicine News Release Exit icon

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An Insider’s Look at Life: Magnified, an Airport Exhibit of Stunning Microscopy Images

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Bubonic plague bacteria on part of the digestive system in a rat flea
What looks like pollen on petals is actually bubonic plague bacteria on the digestive spines of a flea, viewed through a powerful microscope. Credit: B. Joseph Hinnebusch, Elizabeth Fischer and Austin Athman, NIH’s National Institute of Allergy and Infectious Diseases.

Science. Art. Airports. I’ve never used those three words together before. But I’ve been doing it a lot lately while working on Life: Magnified, an exhibit of 46 striking scientific images created by scientists around the country using state-of-the-art microscopes.

The show is at Washington Dulles International Airport, where more than a million travelers will see it over its 6-month run. As our director said in a recent post on another NIGMS blog, “What a great way to share the complexity and beauty of biomedical science with such a large public audience!”

We’ve also set up an online gallery, where the colorful images can be viewed and freely downloaded for research, educational and news media purposes.

The project itself was quite an adventure. When we asked scientists to send us images, our fears of not getting enough attractive, high-resolution options were drowned by a deluge of more than 600 submissions. Then we worried how to sort through them all and make final selections. Doing so required several rounds of online viewing, various ranking systems and a panel of experts. Then the images were printed as large, digital negatives on transparency film.

Artist's rendition of a network diagram. Credit: Allison Kudla, Institute for Systems Biology.
The midnight installation of Life: Magnified involved five people (that’s me in pink), a ladder and lots of rags and glass cleaner. Credit: Woody Machalek.

Dulles is a pretty busy place, so we set up the exhibit when it was quietest—the middle of the night (10 p.m. to 1:30 a.m., to be exact). We swapped out images from the previous photography exhibit and installed the Life: Magnified ones in LED lightboxes mounted in the airport’s Gateway Gallery. It was an eerie and exhilarating feeling to be in a noiseless, nearly empty airport without heavy bags and a long walk to a departure gate.

Less than 12 hours later, I was surprised to receive an e-mail from someone who had passed through the exhibit and sent a few photos. He called the images “stunning.” Similar sentiments were expressed by Science, NBC News online Exit icon, The Atlantic Exit icon, The Washington Post Exit icon, National Geographic Exit icon and other publications.

Now I’m being asked about next steps, including whether the exhibit will travel. We’re investigating a variety of options. For now, I hope you’re able to see the exhibit in person. If not, take a look at the images online and see which ones you enjoy most.

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Cool Image: Researching Regeneration in a Model Organism

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The isolated feeding tube of a flatworm.

The feeding tube, or pharynx, of a planarian worm with cilia shown in red and muscle fibers shown in green. Credit: Carrie Adler/Stowers Institute for Medical Research.

This rainbow-hued image shows the isolated feeding tube, or pharynx, of a tiny freshwater flatworm called a planarian, with the hairlike cilia in red and muscle fibers in green. Scientists use these wondrous worms, which have an almost infinite capacity to regrow all organs, as a simple model system for studying regeneration. A research team led by Alejandro Sánchez Alvarado of the Stowers Institute for Medical Research exploited a method known as selective chemical amputation to remove the pharynx easily and reliably. This allowed the team to conduct a large-scale genetic analysis of how stem cells in a planaria fragment realize what’s missing and then restore it. The researchers initially identified about 350 genes that were activated as a result of amputation. They then suppressed those genes one by one and observed the worms until they pinpointed one gene in particular—a master regulator called FoxA—whose absence completely blocked pharynx regeneration. Scientists believe that researching regeneration in flatworms first is a good way to gain knowledge that could one day be applied to promoting regeneration in mammals.

Learn more:
Stowers Institute News Release
Sánchez Lab

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The Inner Life of Nerve Cells

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“Before this research, we didn’t even know that neurons had this special mechanism to control neuropeptide function. This is why we do basic research. This is why it’s important to understand how neurons work, down to the subcellular and molecular levels.”—Kenneth Miller”

Nerve cells (neurons) in the brain use small molecules called neuropeptides to converse with each other. Disruption of this communication can lead to problems with learning, memory and other brain functions. Through genetic studies in a model organism, the tiny worm C. elegans, a team led by Kenneth Miller of the Oklahoma Medical Research Foundation has uncovered a previously unknown mechanism that nerve cells use to package, move and release neuropeptides. The researchers found that a protein called CaM kinase II, which plays many roles in the brain, helps control this mechanism. Neuropeptides in worms lacking CaM kinase II spilled out from their packages before they reached their proper destinations. A more thorough understanding of how neurons work, provided by studies like this, may help researchers better target drugs to treat memory disorders and other neurological problems in humans.

This work also was funded by NIH’s National Institute of Mental Health.

Learn more:
Oklahoma Medical Research Foundation News Release Exit icon
Using Model Organisms to Study Health and Disease Fact Sheet