The stunning pigmentation of tigers, the massive jaws of sharks, and the hyper-acute vision of eagles. These and other remarkable features of higher organisms (vertebrates) derive from a small group of powerful cells, called neural crest cells, that arose more than 500 million years ago. Molecular biologist Carole LaBonne of Northwestern University in Illinois studies how neural crest cells help give rise to these important vertebrate structures throughout development.
Very early during embryonic development, stem cells differentiate into different layers: mesoderm, endoderm, and ectoderm. Each of these layers then gives rise to different cell and tissue types. For example, the ectoderm becomes skin and nerve cells. Mesoderm turns into muscle, bone, fat, blood and the circulatory system. Endoderm forms internal structures such as lungs and digestive organs.
These three layers are present in vertebrates—animals with a backbone and well-defined heads, such as fish, birds, reptiles, and mammals—as well as animals without backbones, such as the marine-dwelling Lancelets and Tunicates (referred to as non-vertebrate chordates). Unlike cells in these layers, neural crest cells, which are found only in vertebrates, don’t specialize until much later in development. The delay gives neural crests cells the extra time and flexibility to sculpt the complex anatomical structures found only in vertebrate animals.
Scientists have long debated how neural crest cells manage to finalize their destiny so much later than all other cell types.
Using the frog Xenopus as a model system, LaBonne and her colleagues performed a series of experiments that revealed the process and identified key genes that control it.
In this video, LaBonne describes the power of neural crest cells and how they can be useful for studies of human health, including how cancer cells can metastasize, or migrate, throughout the body.
Dr. LaBonne’s research is funded in part by NIGMS grant 5R01GM116538.
About 10 years ago, University of Utah geneticist Mark Yandell developed a software platform called VAAST (Variant Annotation, Analysis & Search Tool) to identify rare genes. VAAST, which was funded by NHGRI, was instrumental in pinpointing the genetic cause of a mystery disease that killed four boys across two generations in an Ogden, UT family.
NIGMS has been supporting Yandell’s creation of the next generation of his software, called VAAST 2, for the past few years. The new version incorporates models of how genetic sequences are conserved among different species to improve accuracy with which benign genetic sequences can be differentiated from disease-causing variations. These improvements can help identify novel disease-causing genes responsible for both rare and common diseases.
Yandell and his colleagues in the Utah Genome Project recently took part in a panel at the Sundance Film Festival called the “Genetics of Storytelling” to discuss film’s ability to convey the power of science and medicine. Yandell told the audience his story about his efforts to use VAAST to trace the Ogden boys’ genetic variation back to their great-great-great-great-great grandmother.
I can still remember that giddy feeling I had seven years ago, when I first read about the “zombie ant.” The story was gruesome and fascinating, and it was everywhere. Even friends and family who aren’t so interested in science knew the basics: in a tropical forest somewhere there’s a fungus that infects an ant and somehow takes control of the ant’s brain, forcing it to leave its colony, crawl up a big leaf, bite down and wait for the sweet relief of death. A grotesque stalk then sprouts from the poor creature’s head, from which fungal spores rain down to infect a new batch of ants.
A fungal fruiting body erupts through the head of a carpenter ant infected by a parasitic fungus in Thailand. Credit: David Hughes, Penn State University.
The problem is, it doesn’t happen quite like that. David Hughes, the Penn State University entomologist who reported his extensive field observations of the fungus/ant interactions in BMC Ecology, which caused much excitement back in 2011, has continued to study the fungus, Ophiocordyceps unliateralis, and its carpenter ant host, Camponotus leonardi.
In late 2017, Hughes and his colleagues published an article in PNAS in which they used sophisticated microscopy and image-processing techniques to describe in great detail how the fungus invades various parts of the ant’s body including muscles in its legs and head.
Although Hughes’s earlier BMC Ecology paper showed fungus in the head of an ant, the new study reveals that the fungus never actually enters the brain.
To me, the new finding somehow made the fungus’ control over the ant even more baffling. What exactly was going on?
To find out, I spoke with Hughes and his graduate student Maridel Fredericksen.
Every one of our thoughts, emotions, sensations, and movements arise from changes in the flow of electricity in the brain. Disruptions to the normal flow of electricity within and between cells is a hallmark of many diseases, especially neurological and cardiac diseases.
The source of electricity within nerve cells (i.e., neurons) is the separation of charge, referred to as voltage, across neuronal membranes. In the past, scientists weren’t able to identify all the molecules that control neuronal voltage. They simply lacked the tools. Now, University of Colorado biologist Joel Kralj has developed a way to overcome this hurdle. His new technique—combining automated imaging tools and genetic manipulation of cells—is designed to measure the electrical contribution of every protein coded by every gene in the human genome. Kralj believes this technology will usher in a new field of “electromics” that will be of enormous benefit to both scientists studying biological processes and clinicians attempting to treat disease.
In 2017, Kralj won a New Innovator Award from the National Institutes of Health for his work on studying voltage in neurons. He is using the grant money to develop a new type of microscope that will be capable of measuring neuronal voltage from hundreds of cells simultaneously. He and his research team will then attempt to identify the genes that encode any of the 20,000 proteins in the human body that are involved in electrical signaling. This laborious process will involve collecting hundreds of nerve cells, genetically removing a single protein from each cell, and using the new microscope to see what happens. If the voltage within a cell is changed in any way when a specific protein is removed, the researchers can conclude that the protein is essential to electrical signaling.
In this video, Kralj discusses how he plans to use his electromics platform to study electricity-generating cells throughout the body, as well as in bacterial cells (see our companion blog post “Feeling Out Bacteria’s Sense of Touch” featuring Kralj’s research for more details).
Dr. Kralj’s work is funded in part by the NIH under grant 1DP2GM123458-01.
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, 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 “Feeling Out Bacteria’s Sense of Touch”
Oxford University. Credit: Andrew Shiva, Wikimedia Commons CC BY-SA.
MARC U-STAR Scholars Jasmine Brown and Naomi Mburu were among 32 Americans to recently receive the prestigious Rhodes Scholarship at Oxford University in England. Rhodes Scholars are chosen for their academic and research achievements, as well as their commitment to others and leadership potential.
As current MARC U-STAR Scholars, Brown and Mburu are part of an NIGMS research training program for undergraduate junior and senior honor students. MARC is designed to increase the number of people from groups underrepresented in biomedical sciences by preparing students for high-caliber, doctorate-level training.
Here’s more about these two distinguished women:
Credit: Joe Angeles, WashU Photos.
Jasmine Brown, 21
Brown, of Hillsborough, New Jersey, is a senior at Washington University in St. Louis and works as a research assistant at the Washington University School of Medicine. There, she studies genes that are protective against mental defects that result from West Nile-induced brain inflammation. After she receives her bachelor’s degree in biology, she plans to earn a doctorate degree in neuroscience as a Rhodes Scholar at Oxford University.
In addition to her current training as a MARC Scholar, Brown has spent her summers as an undergraduate research assistant, engaging in the study of these other notable subjects:
Lung cancer, at the Broad Institute of MIT and Harvard (2017)
Specific drugs’ cough-suppressing effects, at Johns Hopkins University School of Medicine (2015)
Long-term neurological effects of cocaine and other stimulants on the teen brain, at the University of Miami Miller School of Medicine (2014)
“What I love about science is that it gives me tools to generate answers and to improve human health. It’s a fun process for me, but also a satisfying one because I can make an impact,” Brown said in a statement.
Equally important to her studies, Brown is a champion for other underrepresented students in the sciences. After her own experience as the target of prejudice, Brown started the Minority Association of Rising Scientists (MARS) to support underrepresented students participating in research and inform faculty members about implicit bias. With the help of the National Science Foundation, Brown is working to expand MARS nationwide.
Brown has given back to the community in other ways. She was a member of The Synapse Project, which prepares high school students for a neuroscience competition called Brain Bee. She was also a 2014-2015 candidate for Mx. WashU, an organization that raises money for a children’s program called City Faces.
Naomi Mburu, 21
Credit: Marlayna Desmond for UMBC.
Naomi Mburu, of Ellicott City, Maryland, is the daughter of Kenyan immigrants and the first student in the history of the University of Maryland Baltimore County (UMBC) to receive the Rhodes Scholarship. The senior in chemical engineering plans to complete a doctorate in engineering science and to research heat transfer applications for nuclear fusion reactors.
“I believe the Rhodes Scholarship will allow me to foster a stronger community amongst my fellow scholars because we will all be attending the same institution,” Mburu said in a statement.
Mburu is currently working with Gymama Slaughter, UMBC associate professor of computer science and electrical engineering, to develop a machine that ensures human organs remain healthy as they await transplant.
During her recent summer internship with Intel, Mburu developed an interactive model to estimate the cost of coatings applied to equipment. Her work helped improve pricing negotiations and established additional cost estimates for other chemical processes.
Her other areas of research have included:
Assessing phosphate’s effects on the ribosomal protein L4 as a student at Mount Hebron High School
Measuring the impurities found in the Large Hadron Collider particle accelerator, at the European Organization for Nuclear Research, Geneva, Switzerland
Mburu’s aspirations involve not just science but education advocacy. Her passion for STEM education and increasing diversity in STEM fields led to her current involvement as a MARC trainee, where she’s learned to communicate her desire to make a global impact through her science research and her efforts to remove barriers to education equality.
In her free time, Mburu has helped K-12 students with their homework during her time at UMBC. She continues to mentor youth and helps high school girls on STEM-related research projects.
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.
Name: Danio rerio Hometown: Freshwater ponds and rivers of India, Nepal, and neighboring countries Occupation: Research Long-term goal: Solving the basic mysteries of life Work site: More than 600 science labs worldwide
That’s me and some other zebrafish, swimming in a tank in one of the more than 600 labs around the world that use us to study embryo development, genetics, and all kinds of human diseases. Credit: Wikimedia Commons, Azul.
Apart from the tell-tale stripes that give me my nickname, zebrafish, I look a lot like your standard minnow swimming in the shallows of any pond, lake, or river. But I like to think I’m more important than that. In fact, researchers around the world have turned to me and my extended family to understand some of the most basic mysteries of life. From studying us, they’re learning about how embryos develop, how cancer works, and whether someday humans might be able to rebuild a heart, repair a spinal cord injury, or regrow a severed limb.
Why us? Because zebrafish are pretty special and researchers think we’re easy to work with. First, unlike your standard lab mouse or rat, we lay lots of eggs, producing baby fish that grow up fast. We develop outside our mothers and go from egg to embryo to free-swimming larva in just 3 days (check out this video of how we grow, cell by cell, during the first 24 hours). Within 3 months, we’re fully mature.
Not only do zebrafish moms have many babies at the same time, and not only do these babies grow up quickly, but our eggs and embryos are see-through, so scientists can literally watch us grow one cell at a time. We stay mostly transparent for a few weeks after hatching. That makes it super easy for scientists to monitor us for both normal and abnormal development. In fact, scientists have learned how to turn off the genes that give our skin its color. These zebrafish, named casper, after the “friendly ghost” of cartoon fame, stay semi-transparent, or translucent, through adulthood.
And last, but certainly not least, did I mention that we can regenerate? If parts of my body are damaged, even to a significant degree, they can regrow. This holds true for my heart, fins, spinal cord, and even brain tissue. Our regenerative capacity is seemingly unlimited; my caudal fin, for example, can grow back dozens of times. Continue reading “Zebrafish Scrapbook”
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 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.
How do you measure pain? A patient’s furrowed brow, a child’s cries or tears—all are signs of pain. But what if the patient suffers from severe dementia and can’t describe what she is feeling or is a young child who can’t yet talk? Caregivers can help read the signs of pain, but their interpretations may differ greatly from patient to patient, because people have different ways of showing discomfort. And when the patient is unconscious, such as during surgery or while in intensive care, the caregiving team has even fewer ways to measure pain.
Assessing pain is an inexact science. It includes both subjective and objective measures. A patient might be asked during a subjective assessment (performed, perhaps, with a caregiver showing a pain-rating scale such as the one in the figure), “How much pain are you feeling today?” That feedback is coupled with biological markers such as an increased heart rate, dilated pupils, sweating, and inflammation as well as blood tests to monitor high levels of the stress hormone cortisol. Combined, these measurements can give doctors a fairly clear picture of how much pain a patient feels.
Patients can point to one of the faces on this subjective pain scale to show caregivers the level of pain they are experiencing. Credit: Wong-Baker Faces Foundation.
But imagine if members of the surgical or caregiving team could actually “see” how the patient is feeling? Such insight would let them select better drugs to use during and after surgery, tailoring care to each patient. That tool could be put into service in the operating room and by the bedside in intensive care, giving nonstop reports of pain as the patient experiences it.
An objective measure of pain also has uses beyond the operating room and intensive care unit. Given the high risk for opioid misuse, such a measure could take the guesswork out of pain management and give doctors a more accurate indication of pain levels to prevent over-prescribing opioid pain relievers.
of Northwestern University in Illinois studies how neural crest cells help give rise to these important vertebrate structures throughout development.
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Patients can point to one of the faces on this subjective pain scale to show caregivers the level of pain they are experiencing. Credit: Wong-Baker Faces Foundation.