Interview with a Scientist: Jeramiah Smith on the Genomic Antics of an Ancient Vertebrate

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,Link to external web site 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).

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The Skull’s Petrous Bone and the Rise of Ancient Human DNA: Q & A with Genetic Archaeologist David Reich

A macro image of the petrous bone. 3 sections are color coded A (green), B (blue), and C (red)The human petrous bone in the skull protects the inner ear structures. Though it is one of the hardest, densest bones in the body, some portions (such as the area in orange, protecting the cochlea) are denser than others. Possibly because the petrous bone is so dense, DNA within the petrous bone is better preserved than in other bones. In some cases, scientists have extracted more than 100 times more DNA from the petrous bone than other bones, including teeth. Credit: Pinhasi et al., 2015, PLOS ONE.

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):

“How the introduction of farming changed the human genome” November 2015

“Fourth strand’ of European ancestry originated with hunter-gatherers isolated by Ice Age” November 2015

“Scientists sequence first ancient Irish human genomes” December 2015

“Genetic studies provide insight into ancient Britain’s diversity” January 2016

“The world’s first farmers were surprisingly diverse” June 2016

“Study reveals Asian ancestry of Pacific islanders” October 2016

“Ancient DNA solves mystery of the Canaanites, reveals the biblical people’s fate” July 2017

“Ancient DNA data fills in thousands of years of human prehistory in Africa” September 2017

“European Hunter-Gatherers Interbred With Farmers From the Near East” November 2017

“Surprise as DNA reveals new group of Native Americans: the ancient Beringians” January 2018

“Ancient DNA reveals genetic replacement despite language continuity in the South Pacific” February 2018

“Stone Age Moroccan Genomes Reveal Sub-Saharan African, Near Eastern Ancestry” March 2018

“Some early modern populations in Britain may have had dark skin” March 2018

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Genomic Gymnastics of a Single-Celled Ciliate and How It Relates to Humans

Laura Landweber
Credit: Denise Applewhite.
Laura Landweber
Grew up in: Princeton, New Jersey
Job site: Columbia University, New York City
Favorite food: Dark chocolate and dark leafy greens
Favorite music: 1940’s style big band jazz
Favorite hobby: Swing dancing
If I weren’t a scientist I would be a: Chocolatier (see “Experiments in Chocolate” sidebar at bottom of story)

One day last fall, molecular biologist Laura Landweber Link to external web site 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.

Oxytricha trifallax cells in the process of mating
Two Oxytricha trifallax cells in the process of mating. Credit, Robert Hammersmith.

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

Interview With a Scientist: Joel Kralj, Electromicist

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 Exit icon 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.

Zebrafish Scrapbook

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
Danio rerio
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 Exit icon 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

“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

Fall 2017 Issue of Findings Magazine

It’s back! Check out the new issue of Findings magazine.

Findings presents cutting-edge research from scientists in diverse biomedical fields. The articles are aimed at high school students with the goal of making science—and the people who do it—interesting and exciting, and to inspire young readers to pursue careers in biomedical research. In addition to putting a face on science, Findings offers activities such as quizzes and crossword puzzles and, in its online version, video interviews with scientists.

The Fall 2017 issue profiles Yale University biologist Enrique De La Cruz, who studies how actin—a protein chain that supports cell structure—breaks so easily. Also profiled is University of California, Berkeley, biologist Rebecca Heald and her study of developmental factors that control an animal’s size.

This issue also features:

  • A virtual reality program designed to help burn patients manage pain
  • The promise of gene therapy for glaucoma
  • The many ways scientists categorize the biological world using “omics”
  • What researchers know—and don’t know—about how general anesthetics work
  • How animation helps researchers visualize interactions between biological molecules
  • How cells use sugary outer coatings to distinguish friend from foe
  • What makes our tissues stiff, squishy, solid, or see-through (hint: its initials are ECM)
  • How super-powerful microscopes are revealing views of biology never possible before

View Findings online, or order a print copy (classroom sets of up to 30 copies are available for educators).

 

Happy Birthday, BioBeat

This month, our blog that highlights NIGMS-funded research turns four years old! For each candle, we thought we’d illuminate an aspect of the blog to offer you, our reader, an insider’s view.

Who are we?

Over the years, the editorial team has included onsite science writers, office interns, staff scientists and guest authors from universities. Kathryn, who’s a regular contributor, writes entirely from her home office. Chris, who has a Ph.D. in neuroscience and now manages the blog, used to do research in a lab. Alisa has worked in NIGMS’ Bethesda-based office the longest: 22 years! She and I remember when we first launched Biomedical Beat as an e-newsletter in 2005. You can read more about each of the writers on the contributors page and if you know someone who’s considering a career in science communications, tell them to drop us a line.

How do we come up with the stories?

We get our story ideas from a range of sources. For instance, newspaper articles about an experimental pest control strategy in Florida and California prompted us to write about NIGMS-funded studies exploring the basic science of the technique. A beautiful visual from a grantee’s institution inspired a short post on tissue regeneration research. And an ongoing conversation with NIGMS scientific staff about the important role of research organisms in biological studies sparked the idea for a playful profile of one such science superstar.

A big change in our storytelling has been shifting the focus from a single finding to broader progress in a lab or field. So instead of reporting on a study just published in a scientific journal, we may write about the scientist’s career path or showcase a collection of recent findings in that particular field. These approaches help us demonstrate that scientific understanding usually progresses through the slow and steady work undertaken by many labs.

What are our favorite posts?

I polled the writers on posts they liked, and the list is really long! Here are the top picks.


Four Ways Inheritance Is More Complex Than Mendel Knew


The Endoplasmic Reticulum: Networking in the Cell


Interview With a Scientist: Janet Iwasa, Molecular Animator


From Basic Research to Bioelectric Medicine


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

What are your favorite posts?

We regularly review data about the number of times a blog post has been viewed to identify the ones that interest readers the most. That information also helps guide our decisions about other topics to feature on the blog. The Cool Image posts are among the most popular! Below are some other chart-topping posts.


Our Complicated Relationship With Viruses


The Proteasome: The Cells Trash Processor in Action


Demystifying General Anesthetics


Meet Sarkis Mazmanian and the Bacteria That Keep Us Healthy


5 Reasons Biologists Love Math

We always like hearing from readers! If there’s a basic biomedical research topic you’d like us to write about, or if you have feedback on a story or the blog in general, please leave your suggestions in the comment field below or email me.

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

Sea Urchin Regeneration May Help Us Understand Aging

Sea urchin

The variegated sea urchin typically lives for about 4 years in the wild. The close-up view shows the sea urchin’s spines and tube feet that regrew after being removed 15 days earlier. Credit: Helena Reinardy (left) and Andrea Bodnar (right), Bermuda Institute of Ocean Sciences.

If you’ve ever been to the beach and walked around the rocks during low tide, you’ve probably seen a sea urchin. You may not have known that sea urchins found along the Pacific shore can live for more than 100 years. What’s even cooler is that, as they age, they don’t seem to lose their abilities to reproduce or regenerate damaged body parts. While different species of sea urchins have varying life expectancies, they all seem to share fountain-of-youth characteristics. For these and other reasons, scientists study sea urchins to investigate aging and other basic life processes. Continue reading