Category: Cells

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New Research Sheds Light on Drug-Induced Salivary Issues

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Open human mouth
Scientists have discovered a possible mechanism behind the bad taste and dry mouth caused by some drugs. Credit: Stock image.

The effects some medicines have on our salivary glands can at times extend beyond the fleeting flavor we experience upon ingesting them. Sometimes drugs cause a prolonged bad taste or dryness in the mouth, both of which can discourage people from taking medicines they need. Now, a research team led by Joanne Wang of the University of Washington has discovered a possible mechanism behind this phenomenon. Working primarily with mice and using a commonly prescribed antidiabetic drug known to impair taste, the scientists identified a protein in salivary gland cells that takes up the drug from the bloodstream and secretes it in saliva. Wang and her colleagues were also able to pinpoint a specific gene that, when removed, hindered this process. They hope their new insights will aid efforts to develop medicines that do not cause salivary issues.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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Cool Image: Training Cells to Devour Dying Neighbors

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A healthy cell that has ingested dying cells.

A healthy cell (green) that has ingested dying cells (purple). Credit: Toru Komatsu, University of Tokyo.

In this image, a healthy cell (green) has engulfed a number of dying cells (purple) just as a predator might ingest wounded or dying prey. A team of researchers is hoping to use this same strategy at the cellular level to help treat infection, neurodegenerative diseases or cancer.

Our bodies routinely use a process called phagocytosis to rid themselves of unhealthy cells. Takanari Inoue at Johns Hopkins University and collaborators at the University of Tokyo set out to investigate the molecular underpinnings of phagocytosis. Their goal was to endow laboratory-grown human cells with phagocytotic skills, namely the ability to recognize, swallow and digest dying cells. The scientists tried to do this by inserting into the cells two molecules known to play a role in phagocytosis.

The engineered cells accomplished the first two tasks—they recognized and surrounded dying cells. But they didn’t digest what they’d engulfed. Now the researchers are looking for a molecular trigger to get the engineered cells to complete this last task.

Eventually, the scientific team aims to build artificial cells that are programmed to target and destroy abnormal cells, such as those ravaged by bacteria, cancer or other diseases.

Learn more:
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How Cells Take Out the Trash Article from Inside Life Science
Cellular Suicide: An Essential Part of Life Article from Inside Life Science

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Say Cheese

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Assorted cheeses
A biofilm of bacteria and fungi, commonly known as a rind, forms on the surface of traditionally aged cheeses. Credit: Elia Ben-Ari.

Biofilms—multispecies communities of microbes that live in and on us, and in the environment—are important for human health and the function of ecosystems. But studying these microbial metropolises can be challenging because many of the environments where they’re found are hard to replicate in the lab.

Enter cheese rinds. These biofilms of bacteria and fungi form on the surface of traditionally aged cheeses, and could serve as a system for understanding how microbial communities form and function. By sequencing DNA from the rinds of 137 artisan cheese varieties collected in 10 countries, Rachel Dutton and her colleagues at Harvard University identified three general types of microbial communities that live on their tasty study subjects. After individually culturing representatives of all the species found in the rind communities the scientists added them to a growth medium that included cheese curd. This approach allowed them to recreate the communities in the lab and use them to detect numerous bacterial-fungal interactions and patterns of community composition over time.

The scientists plan to use their lab-grown cheese rinds to study whether and how various microbes compete or cooperate as they form communities, as well as what molecules and mechanisms are involved. In addition to answering fundamental questions about microbial ecology, this cheesy research might ultimately yield insights that help fight infection-causing biofilms or lead to the discovery of new antibiotics.

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Dutton Lab Exit icon

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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
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 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.

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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.

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Albert Einstein College of Medicine News Release Exit icon