Kathryn Calkins

About Kathryn Calkins

Kathryn Calkins, a long-time reporter for a weekly biotechnology newsletter, is always looking for the best way to share her enthusiasm for the biological sciences.

CLAMP Helps Lung Cells Pull Together

ALT TEXTCells covered with cilia (red strands) on the surface of frog embryos. Credit: The Mitchell Lab.

The outermost cells that line blood vessels, lungs, and other organs also act like guards, alert and ready to thwart pathogens, toxins, and other invaders that can do us harm. Called epithelial cells, they don’t just lie passively in place. Instead, they communicate with each other and organize their internal structures in a single direction, like a precisely drilled platoon of soldiers lining up together and facing the same way.

Lining up this way is crucial during early development, when tissues and organs are forming and settling into their final positions in the developing body. In fact, failure to line up in the correct way is linked to numerous birth defects. In the lungs, for instance, epithelial cells’ ability to synchronize with one another is important since these cells have special responsibilities such as carrying mucus up and out of lung tissue. When these cells can’t coordinate their functions, disease results.

Some lung epithelial cells are covered in many tiny, hair-like structures called cilia. All the cilia on lung epithelial cells must move uniformly in a tightly choreographed way to be effective in their mucus-clearing job. This is a unique example of a process called planar cell polarity (PCP) that occurs in cells throughout the body. Researchers are seeking to identify the signals cells use to implement PCP. Continue reading

Pericytes: Capillary Guardians in the Brain

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The long arms of pericytes cells (red) stretch along capillaries (blue) in a mouse brain. Credit: Andy Shih.

Nerve cells, or neurons, in our brains do amazing work, from telling our hearts to beat to storing our memories. But neurons cannot operate alone. Many kinds of cells support and regulate neurons and—like neurons—they can come under attack due to injuries or disorders, such as stroke or Alzheimer’s disease. Learning what jobs these cells do and how they respond to disease may show researchers new ways to treat central nervous system disorders. One type of support cell, the pericyte, plays some key roles in brain health. These cells are readily adaptable, even in adult brains, and can support a variety of functions.

Pericytes help with blood flow to nerve cells in the brain. They lie wrapped all along the huge networks of capillaries—the tiniest blood vessels—that both feed neurons and form the blood-brain barrier, which filters out certain substances from blood to protect the brain. Pericytes have a body that appears as a bump protruding from a capillary surface. Pericytes also have long thin arms that stretch along each capillary like a snake on a tree branch. These arms, called processes, reach almost to where the next pericyte process begins, without overlapping. This creates a pericyte chain that covers nearly the entire capillary network.

Pericytes are critical for blood vessel stability and blood-brain barrier function. They’re also known to die off as a result of trauma and disease. Andy ShihLink to external web site, Andree-Ann Berthiaume, and colleagues at the Medical University of South Carolina in Charleston, set up an imaging technique in mouse brains that allowed them to see what pericytes do under normal conditions as well as how these cells respond when some are damaged.

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Cellular Footprints: Tracing How Cells Move

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An engineered cell (green) in a fruit fly follicle (red), or egg case, leaves a trail of fluorescent material as it moves across a fruit fly egg chamber, allowing scientists to trace its path and measure how long it took to complete its journey. Credit: David Bilder, University of California, Berkeley.

Cells are the basis of the living world. Our cells make up the tissues and organs of our bodies. Bacteria are also cells, living sometimes alone and sometimes in groups called biofilms. We think of cells mostly as staying in one spot, quietly doing their work. But in many situations, cells move, often very quickly. For example, when you get a cut, infection-fighting cells rally to the site, ready to gobble up bacterial intruders. Then, platelet cells along with proteins from blood gather and form a clot to stop any bleeding. And finally, skin cells surrounding the wound lay down scaffolding before gliding across the cut to close the wound.

This remarkable organization and timing is evident right from the start. Cells migrate within the embryo as it develops so that body tissues and organs end up in the right places. Harmful cells use movement as well, as when cells move and spread (metastasize) from an original cancer tumor to other parts of the body. Learning how and why cells move could give scientists new ways to guide those cells or turn off or slow down the movement when needed.

Glowing Breadcrumbs

Scientists studying how humans and animals form, from a single cell at conception to a complex body at birth, are particularly interested in how and when cells move. They use research organisms like the fruit fly, Drosophila, to watch movements by small populations of cells. Still, watching cells migrate inside a living fly is challenging because the tissue is too dense to see individual cell movement. But moving those cells to a dish in the lab might cause them to behave differently than they do inside the fly. To solve this problem, NIGMS-funded researcher David BilderLink to external web site and colleagues at the University of California, Berkeley, came up with a way to alter fly cells so they could track how the cells behave without removing them from the fly. They engineered the cells to lay down a glowing track of proteins behind them as they moved, leaving a traceable path through the fly’s tissue. The technique, called M-TRAIL (matrix-labeling technique for real-time and inferred location), allows the researchers to see where a cell travels and how long it takes to get there.

Bilder and his team first used M-TRAIL in flies to confirm the results of past studies of Drosophila ovaries in the lab using other imaging techniques. In addition, they found that M-TRAIL could be used to study a variety of cell types. The new technique also could allow a cell’s movement to be tracked over a longer period than other imaging techniques, which become toxic to cells in just a few hours. This is important, because cells often migrate for days to reach their final destinations.

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Feeling Out Bacteria’s Sense of Touch

Our sense of touch provides us with bits of information about our surroundings that inform the decisions we make. When we touch something, our nervous system transmits signals through nerve endings that feed information to our brain. This enables us to sense the stimulus and take the appropriate action, like drawing back quickly when we touch a hot stovetop.

Bacteria are single cells and lack a nervous system. But like us, they rely on their “sense” of touch to make decisions—or at least change their behavior. For example, bacteria’s sense of touch is believed to trigger the cells to form colonies, called biofilms, on surfaces they make contact with. Bacteria may form biofilms as a way to defend themselves, share limited nutrients, or simply to prevent being washed away in a flowing liquid.

Humans can be harmed by biofilms because these colonies serve as a reservoir of disease-causing cells that are responsible for high rates of human infection. Biofilms can protect at least some cells from being affected by antibiotics. The surviving reservoir of bacteria then have more time to evolve resistance to antibiotics.

At the same time, some biofilms can be valuable; for example, they help to break down waste in water treatment plants and to drive electrical current as part of microbial fuel cells.

Until recently, scientists thought that bacteria formed biofilms and caused infections in response to chemical signals they received from their environments. But research in 2014 showed that the bacterium Pseudomonas aeruginosa could infect a variety of living tissues—from plants to many kinds of animals—simply by making contact with them. In the past year, multiple groups of investigators have learned more about how bacteria sense that they have touched a surface and how that sense translates to changes in their behavior. This understanding could lead to new ways of preventing infections or harmful biofilm formation.

Making Contact

Pili (green) on cells from the bacterium Caulobacter crescentus (orange). Scientists used a fluorescent dye to stain pili so they could watch the structures extend and retract. Credit: Courtney Ellison, Indiana University.

When they first make contact with a surface, bacteria change from free-ranging, swimming cells to stationary ones that secrete a sticky substance, tethering them in one place. To form a biofilm, they begin replicating, creating an organized mass stable enough to resist shaking and to repel potential invaders (see https://biobeat.nigms.nih.gov/2017/01/cool-image-inside-a-biofilm-build-up/).

How do swimming bacteria sense that they have found a potential surface to colonize? Working with the bacterium Caulobacter crescentus, Indiana University Ph.D. student Courtney Ellison and her colleagues, under the direction of professor of biology and NIGMS grantee Yves Brun Exit icon, recently showed that hair-like structures on the cell’s surface, called pili, play a role here. The researchers found that as a bacterial cell swims in a fluid, its pili are constantly stretching out and retracting. When the cell makes contact with a surface, the pili stop moving, start producing a sticky substance and use it to hold onto the surface. Continue reading

The Changing Needs of a Cell: No Membrane? No Problem!

Russian nesting dolls. Credit: iStock.

How “membrane-less” organelles help with key cellular functions

Scientists have long known that animal and plant cells have specialized subdivisions called organelles. These organelles are surrounded by a semi-permeable barrier, called a membrane, that both organizes the organelles and insulates them from the rest of the cell’s mix of proteins, salt, and water. This set-up helps to make cells efficient and productive, aiding in energy production and other specialized functions. But, because of their semi-permeable membranes, organelles can’t regroup and reform in response to stress or other outside changes. Cells need a rapid response team working alongside the membrane-bound organelles to meet these fluctuating needs. Until recently, who those rapid responders were and how they worked has been a mystery.

Recent research has led biologists to learn that the inside of a cell or an organelle is not just a lot of different molecules dissolved in water. Instead, we now know that cells contain many pockets of liquid droplets (one type of liquid surrounded by a liquid of different density) with specialized composition and function that are not surrounded by membranes. Because these “membrane-less organelles” are not confined, they can rapidly come together in response to chemical signals, such as those that indicate stress, and equally rapidly fall apart when they are no longer needed, or when the cell is about to divide. This enables membrane-less organelles to be “rapid responders.” They can have complex, multilayered structures that help them to perform many critical cell functions with multiple steps, just like membrane-bound organelles. Scientists even suspect that the way these organelles form as droplets may shed light on how life on Earth first took shape (see sidebar “Could This Be How Life First Took Shape?” at bottom of page).

The Many Membrane-less Organelles

Scientists have identified more than a dozen membrane-less organelles at work in mammalian cells. Several kinds found inside the nucleus—including nuclear speckles, paraspeckles, and Cajal bodies—help with cell growth, stress response, the metabolizing (breaking down) of RNA, and the control of gene expression—the process by which information in a gene is used in the synthesis of a protein. Out in the cytoplasm, P-bodies, germ granules, and stress granules are membrane-less organelles that are involved in metabolizing or protecting messenger RNA (mRNA), controlling which mRNAs are made into proteins, and in maintaining balance, or homeostasis, of the cell’s overall health.

The nucleolus, located inside the nucleus, is probably the largest of the membrane-less organelles. It acts as a factory to assemble ribosomes, the giant molecular machines that “translate” messenger RNAs to make all cellular proteins. Continue reading

“Selfish” Gene Enhances Own Transmission at Expense of Organism’s Fertility

These glowing images of yeast (Schizosaccharomyces kambucha) reproductive cells show an example of a selfish gene at work.
These glowing images of yeast (Schizosaccharomyces kambucha) reproductive cells show an example of a selfish gene at work. Here, the selfish gene boosts its chances of being passed to the next generation by producing both a toxin (stained cyan) and an antitoxin (stained magenta). Cells with a copy of the selfish gene are protected by the antitoxin, left and bottom ovals. Those without the selfish gene are destroyed by the toxin. Scientists suspect that selfish genes could be operating throughout many organisms’ genomes, possibly having a major impact on how genetic material is inherited over generations. Credit: Image courtesy of María Angélica Bravo Núñez and Nicole Nuckolls.

There’s an old saying that rules are meant to be broken. In the 1860s, Gregor Mendel found that each copy of a gene in an organism has an equal chance of being passed to the next generation. According to this simple rule, each version of a gene gets passed to offspring with the same frequency. The natural selection process can then operate efficiently, favoring the genes that produce an advantage for an organism’s survival or reproductive success and, over successive generations, eliminating genes from the gene pool that bring a disadvantage.

Of course, the way organisms inherit genes is not as straightforward as Mendel’s work predicted. In natural systems, inheritance often fails to follow the rules. One culprit scientists are identifying again and again are what are called “selfish genes”: one or more genes that have evolved a method of skewing inheritance in their favor.

Scientists refer to these selfish genes—which are often complexes of multiple genes working together—as “selfish” because they enhance their own transmission to the next generation, sometimes by killing off any of the organism’s reproductive cells that lack copies of those genes. Using a variety of techniques, the genes are effective at passing themselves on to future generations. However, their methods set up a conflict within the organism by damaging its fertility; overall, fewer reproductive cells or offspring survive to produce a new generation.

Selfish genes are a challenge for scientists to identify, but researchers say that knowing more about these genes could help explain a range of genetic mysteries, from causes of infertility to details on how species evolve. The methods these genes use could also be harnessed to help control the reproduction of certain populations such as mosquitos that spread disease.

One recently described selfish gene system is found in the yeast cells pictured above. Sarah Zanders Exit icon and her colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, and the Fred Hutchinson Cancer Research Center in Seattle, Washington, study selfish gene systems in yeast to understand how common they are and how they affect a species’ fertility and evolution. “Usually we think about infertility stemming from the good guys failing. For example, a gene that normally promotes fertility could be mutated so that it can no longer do its job,” says Zanders. “But selfish genes are another potential source of infertility. Learning general principles about selfish genes in simple models will guide future searches for selfish genes that could be contributing to human infertility.”

Recently, the scientists discovered a single selfish gene, wtf4, that encodes both a toxin and an antitoxin protein. When yeast produce their reproductive cells, called spores, the wtf4 toxin protein is released into the immediate vicinity, but the antitoxin remains inside spores that contain a copy of wtf4. The toxin destroys all the spores that don’t have the antitoxin protein. Although the yeast has fewer spores—and therefore reduced fertility—each spore carries wtf4, ensuring that the gene will be passed to the next generation of yeast. Continue reading

Cool Image: Biological Bubbles

Cells are in the process of pinching off parts of their membranes to produce bubbles filled with a mix of proteins and RNAs. Researchers are harnessing this process to develop better drug delivery techniques. The image, courtesy of Chi Zhao, David Busch, Connor Vershel and Jeanne Stachowiak of the University of Texas at Austin, was entered in the Biophysical Society’s 2017 Art of Science Image contest and featured on the NIH Director’s Blog.

This fiery-looking image shows animal cells caught in the act of making bubbles, or blebbing.

Certain cells regularly pinch off parts of their membranes to produce bubbles filled with a mix of proteins and RNAs. The green and yellow portions in the image show the cell membranes as they separate from the cell’s skeleton and bleb from the main cell. The bubbles, shown in red, are called plasma-derived membrane vesicles, or PMVs. PMVs can travel to other parts of the body where they may aid in cell-to-cell communication.

The University of Texas at Austin researchers who produced this image are exploring ways to use PMVs to deliver medicines to precise locations in the body.

Blebbing for Drug Delivery

Drug delivery research tries to find ways to carry medicines to only the tissues in the body that need them with the goal of reducing side effects. To achieve this, delivery methods need to recognize just the cells they target, usually by finding a unique protein on the cell’s surface. Scientists can make proteins that recognize and attach to targets such as cancer cells, but they’ve had trouble attaching medicines to the proteins they made. To get around this problem, scientists could employ PMV-making cells in a laboratory, perhaps even cells taken from a patient who is receiving treatment. They could engineer the cells to make the targeting proteins and then attach the targeting proteins to the PMV surface. The cell’s own protein-making machinery does the hardest job.

The Texas scientists have engineered such donor cells with proteins on their surfaces that precisely target certain kinds of breast cancer cells. When the donor cells are induced to bleb, they produce PMVs laden with the target proteins that locate and bind to the cancer cells.

Researchers hope that eventually PMVs with surface targeting proteins could be filled with medicines and infused into the patient to deliver the drugs specifically to cancerous cells while leaving healthy tissues untouched. Research will continue to investigate this possibility.

This research was funded in part by NIH under grant R01GM112065.

Viruses: Manufacturing Tycoons?

Pseudomonas chlororaphis

A computer image shows a bacterial cell invaded by a virus. The virus uses the cell to copy itself many times. It has built a protein compartment (red, rough circle surrounding the center) to house its DNA. Viral heads (blue, smaller pentagonal shapes spread through out) and tails (pink, rod shaped near the edges) are essential parts of a finished viral particle. The small, light blue particles are the bacterium’s own protein-making ribosomes. Credit: Vorrapon Chaikeeratisak, Kanika Khanna, Axel Brilot and Katrina Nguyen.

As inventors and factory owners learned during the Industrial Revolution, the best way to manufacture a lot of products is with an assembly line that follows a set of precisely organized steps employing many copies of identical and interchangeable parts. Some viruses are among life’s original mass producers: They use sophisticated organization principles to turn bacterial cells into virus particle factories.

Scientists at the University of California, San Diego, and the University of California, San Francisco, used cutting-edge techniques to watch a bacteria-infecting virus (bacteriophage) set up its particle-making factory inside a host cell.

The image above shows this happening inside a Pseudomonas chlororaphis, a soil-borne bacterium that protects plants against fungal pathogens. The virus builds a compartment (red, rough circle surrounding the center) that helps organize an assembly line for making copies of itself. The compartment looks like a cell nucleus, which bacteria do not have, and it functions like a nucleus by keeping activities that directly involve DNA separate from other cellular functions. Continue reading

The Drama of Cell Death

spermatids

Spermatids—one stage in the formation of sperm—in the fruit fly (Drosophila). Credit: Sigi Benjamin-Hong, Rockefeller University (modified).

Although it looks like a bursting firework from a Fourth of July celebration, this image actually was created from pictures of spermatids—one stage in the formation of sperm—in the fruit fly (Drosophila). Drosophila is an organism that scientists often use as a model for studying how cells accomplish their amazing tasks. Drosophila studies can help reveal where an essential cellular process goes wrong in diseases such as autoimmune conditions or cancer. Cell death, or apoptosis, is one of these processes.

Almost every animal cell has the ability to destroy itself via apoptosis. Apoptosis is important because it allows the body both to develop normally and get rid of dangerous and unwanted cells when it needs to later in life, such as when cells become cancerous. Many different signals both within and outside the cell influence whether apoptosis happens when it should, and abnormal regulation of this process is associated with some diseases. Hermann Steller Exit icon and colleagues at Rockefeller University in New York City study Drosophila and mammalian cells to tease apart the steps of apoptosis and the many molecular signals that regulate it. Continue reading

Flipping the Switch on Controlling Disease-Carrying Insects

Illustration of some of the jobs that the ER performs in the cell.

This image shows a mosquito egg. Wolbachia bacteria, which infect many species of insects including mosquitos, move from one generation to the next inside insect eggs. Credit: Wikimedia Commons, Mogana Das Murtey and Patchamuthu Ramasamy, Universiti Sains, Malaysia.

Suppressing insects that spread disease is an essential public health effort, and scientists are testing a possible new tool to use in this challenging arena. They’re harnessing a microbe capable of controlling insects’ reproductive processes.

The microbes, called Wolbachia, live inside the cells of about two-thirds of insect species worldwide, and they can manipulate the host’s reproductive cells in ways that boost their own survival. Scientists think they can use Wolbachia’s methods to reduce populations of insects that spread disease among humans.

A Switch to Control Fertility

Wolbachia have evolved complex ways to control insect reproduction so as to infect increasing numbers of an insect species—such as those prolific disease-spreaders, mosquitos. One method Wolbachia uses is called cytoplasmic incompatibility, or CI. The end result of CI, basically, is that the sperm of infected male insects cause sterility in uninfected females.

Wolbachia that have infected male insects can insert proteins that produce a kind of infertility switch into the host’s sperm. When the sperm later fuses with an egg from an uninfected female, the switch is triggered and renders the egg sterile. If the female is already infected, her eggs will contain Wolbachia, which can turn off the switch and allow the egg to develop. This trick ensures that more Wolbachia-infected insects will survive and continue to reproduce, while uninfected ones will be less successful.

Already, some states Exit icon and countries Exit icon are releasing Wolbachia-infected male mosquitoes into wild mosquito populations that carry disease-causing viruses to test this strategy for insect control. Males carrying a Wolbachia strain that strongly induces infertility in uninfected females should reduce the numbers of mosquito eggs that mature, leading to fewer mosquitos. Continue reading