Many researchers who search for anti-cancer drugs have labs filled with chemicals and tissue samples. Not Rommie Amaro . Her work uses computers to analyze the shape and behavior of a protein called p53. Defective versions of p53 are associated with more human cancers than any other malfunctioning protein.
The United States is in the midst of an opioid overdose epidemic. The rates of opioid addiction, babies born addicted to opioids, and overdoses have skyrocketed in the past decade. No population has been hit harder than rural communities. Many of these communities are in states with historically low levels of funding from the National Institutes of Health (NIH). NIGMS’ Institutional Development Award (IDeA) program builds research capacities in these states by supporting basic, clinical, and translational research, as well as faculty development and infrastructure improvements. IDeA-funded programs in many states have begun prioritizing research focused on reducing the burden of opioid addiction. Below is a snapshot of three of these programs, and how they are working to help their communities:
Because there are generally fewer treatment resources in rural areas compared to larger cities, it can take longer for people addicted to opioids in rural settings to get the care they need. The Vermont Center on Behavior and Health works to address this need and its major implications.
“One very disconcerting trend we’re seeing with this recent crisis is that opioid-addicted individuals are being placed on wait lists lasting months to a year without any kind of treatment,” says Vermont Center on Behavior and Health director Stephen Higgins. “And it’s very unlikely that anyone who is opioid addicted is just going to abstain while they are on a wait list.”
In urban areas, buprenorphine—an approved medication for opioid addiction that can prevent or reduce withdrawal symptoms—is generally dispensed by trained physicians at treatment clinics. Unfortunately, many rural communities don’t have enough physicians and clinics to serve patients in need. While waiting for treatment, patients are at risk of premature death, overdose, and contracting diseases such as HIV.
Stacey Sigmon, a faculty member in the Vermont Center on Behavior Health, has developed a method to help tackle this problem: a modified version of a tamper-proof device that delivers daily doses of buprenorphine. The advantage of using the modified device is that it makes each day’s dose available during a preprogrammed 3-hour window within the patient’s home, eliminating the need to visit a clinic.
During a study, participants in the treatment group received interim buprenorphine from the device. They also received daily calls to assess drug use, craving, and withdrawal. Participants in the control group didn’t receive buprenorphine. They remained on the waiting list of their local clinic and didn’t receive phone calls. The results, published in the New England Journal of Medicine (NEJM), indicate that the device works. Participants who received the interim buprenorphine treatment submitted a higher percentage of drug test specimens that were negative for opioids than those in the control group at 4 weeks (88 percent vs. 0 percent), 8 weeks (84 percent vs. 0 percent), and 12 weeks (68 percent vs. 0 percent). Sigmon and colleagues are currently testing the device with a much larger group of participants.
“This tool is now available to other rural states that are also being devastated by this crisis and are not so far along in beefing up treatment capacity,” says Higgins.
While DNA acts as the hard drive of the cell, storing the instructions to make all of the proteins the cell needs to carry out its various duties, another type of genetic material, RNA, takes on a wide variety of tasks, including gene regulation, protein synthesis, and sensing of metals and metabolites. Each of these jobs is handled by a slightly different molecule of RNA. But what determines which job a certain RNA molecule is tasked with? Primarily its shape. Julius Lucks, a biological and chemical engineer at Northwestern University, and his team study the many ways in which RNA can bend itself into new shapes and how those shapes dictate the jobs the RNA molecule can take on.
The first known descriptions of cancer come from ancient Egypt more than 3,500 years ago. Early physicians attributed the disease to several factors, including an imbalance in the body’s humoral fluids, trauma, and parasites. Only in the past 50 years or so have we figured out that mutations in critical genes are often the trigger. The sea lamprey, a slimy, snake-like blood sucker, is proving to be an ideal tool for understanding these mutations.
The sea lamprey, often called the jawless fish, is an ancient vertebrate whose ancestor diverged from the other vertebrate lineages (fish, reptiles, birds and mammals) more than 500 million years ago. Jeramiah Smith, associate professor of biology at the University of Kentucky, has discovered that lamprey have two separate genomes: a complete genome specific to their reproductive cells, consisting of 99 chromosomes (humans have 23 pairs) and another genome in which about 20 percent of genes have been deleted after development. Using the lamprey model, Smith and his colleagues have learned that many of these deleted genes—such as those that initiate growth pathways—are similar to human oncogenes (i.e., cancer-causing genes).
For the past few decades, new evidence about ancient humans—in the form of skeletal remains, tools, and other artifacts—has trickled in, inching us closer to an understanding of how our species evolved and spread out across the planet. In just the past few years, however, knowledge of our deep past expanded significantly thanks to a series of technological breakthroughs in sequencing of ancient human genomes. This technology can be used to find genetic links among populations of human ancestors dating back hundreds of thousands of years.
In addition to advances in genomic technology, another factor is driving the explosion of new discoveries—an inch-long section of the human skull. Found near our ears, this pyramid-shaped portion of the temporal bone is nicknamed the petrous bone. The bone is very hard, possibly because it needs to protect fragile structures such as the cochlea, which translates sound into brain signals, and the semicircular canals, which help us maintain our balance. Perhaps because the petrous bone is so dense, it also is the bone in the body that best preserves DNA after a person dies. As a result, archaeologists are scrambling to study samples taken from this pyramid-shaped structure to unlock the mysteries of our species’ formative years.
Here’s a sampling of headlines declaring new findings about ancient peoples from around the globe that were based on genetic information obtained from the petrous bone (NIGMS-funded research indicated in black):
One day last fall, molecular biologist Laura Landweber surveyed the Princeton University lab where she’d worked for 22 years. She and her team members had spent many hours that day laboriously affixing yellow Post-it notes to the laboratory equipment—microscopes, centrifuges, computers—they would bring with them to Columbia University, where Landweber had just been appointed full professor. Each Post-it specified the machinery’s location in the new lab. Items that would be left behind—glassware, chemical solutions, furniture, office supplies—were left unlabeled.
As Landweber viewed the lab, decorated with a field of sunny squares, her thoughts turned to another sorting process—the one used by her primary research subject, a microscopic organism, to sift through excess DNA following mating. Rather than using Post-it notes, the creature, a type of single-celled organism called a ciliate, uses small pieces of RNA to tag which bits of genetic material to keep and which to toss.
Landweber is particularly fond of Oxytricha trifallax, a ciliate with relatives that live in soil, ponds and oceans all over the world. The kidney-shaped cell is covered with hair-like projections called cilia that help it move around and devour bacteria and algae. Oxytricha is not only bizarre in appearance, it’s also genetically creative.
Unlike humans, whose cells are programmed to die rather than pass on genomic errors, Oxytricha cells appear to delight in genomic chaos. During sexual reproduction, the ciliate shatters the DNA in one of its two nuclei into hundreds of thousands of pieces, descrambles the DNA letters, throws most away, then recombines the rest to create a new genome.
Landweber has set out to understand how—and possibly why—Oxytricha performs these unusual genomic acrobatics. Ultimately, she hopes that learning how Oxytricha rearranges its genome can illuminate some of the events that go awry during cancer, a disease in which the genome often suffers significant reorganization and damage.
Oxytricha’s Unique Features
Oxytricha carries two separate nuclei—a macronucleus and a micronucleus. The macronucleus, by far the larger of the two, functions like a typical genome, the source of gene transcription for proteins. The tiny micronucleus only sees action occasionally, when Oxytricha reproduces sexually.
What really makes Oxytricha stand out is what it does with its DNA during the rare occasions that it has sex. When food is readily available, Oxytricha procreates without a partner, like a plant grown from a cutting. But when food is scarce, or the cell is stressed, it seeks a mate. When two Oxytricha cells mate, the micronuclear genomes in each cell swap DNA, then replicate. One copy of the new hybrid micronucleus remains intact, while the other breaks its DNA into hundreds of thousands of pieces, some of which are tagged, recombined, then copied another thousand-fold to form a new macronucleus. Continue reading
Both of the cells above can scoot across a microscope slide equally well. But when it comes to moving in 3D, the one without the red blob in the center (the nucleus) stalls out. That’s sort of like an Olympic speed skater who wouldn’t be able to perform even a single leap in a figure skating competition.
Scientists have known for some time that the nucleus is involved in moving cells across a flat surface—it slides to one side of the cell and “pushes” from behind. However, scientists have also shown that cells with their nuclei removed can migrate along a flat surface just as well as their brethren with intact nuclei. But they had no idea that, without a nucleus, a cell could no longer move in three dimensions.
This discovery was made by UNC-Chapel Hill biologists Keith Burridge and James Bear and their colleagues. These NIGMS-funded researchers also observed that cells whose nuclei had been disconnected from the cytoskeleton could not move through 3D matrices. The cytoskeleton is the microscopic network of actin protein filaments and tubules in the cytoplasm of many cells that provides the cell’s shape and coherence. It has also has been thought to play a major role in cell movement.
The researchers speculate that the reason cells without nuclei (or those whose nuclei have been disconnected from the cytoskeleton) don’t navigate in 3D has to do with complex mechanical interactions between the cytoskeleton and the nucleoskeleton. The nucleoskeleton is a molecular scaffold within the nucleus supporting many functions such as DNA replication and transcription, chromatin remodeling, and mRNA synthesis. The interface between the cytoskeleton and nucleoskeleton consists of interlocking proteins that together provide the physical traction that cells need to push their way through 3D environments. Disrupting this interface is the equivalent of breaking the clutch in a car: the motor revs, but the wheels don’t spin, and the car goes nowhere.
A better understanding of the physical connections between the nucleus and the cytoskeleton and how they influence cell migration may provide additional insight into the role of the nucleus in diseases, such as cancer, in which the DNA-containing organelle is damaged or corrupted.
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.
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.