Poison dart frogs tend to advertise their toxic nature with a brightly colored skin. The toxic chemical made by those frogs can kill a human. It does not, however, harm the frog. A new study shows that for some frogs, evolving a way to make and use this defensive weapon came with a price.
A genetic change protected one group of frogs from epibatidine (Ep-ih-BAT-ih-deen). It’s a lethal toxin that the frogs derive by recycling some toxic materials in their diet. But the change that keeps the frogs from being poisoned by this chemical also disrupts a key chemical — one that relays messages in its brain. The frogs have managed to sidestep that potentially damaging side effect, however. It required evolving some additional genetic tweaks. Researchers describe what those tweaks are in the September 22 Science.
Other studies had turned up genetic changes that help frogs resist the toxic effects of certain toxins. But this study “lets you look under the hood,” says Butch Brodie. He’s an evolutionary biologist at the University of Virginia in Charlottesville. He wasn’t involved in the research. But with this study, he notes, it’s possible see the full effects of those changes.
Many poison dart frogs carry cocktails of toxic alkaloids, a type of chemical, in their skin. It defends them from being eaten by predators. The ingredients to make those toxins are picked up through the frogs’ diet. And the toxin can vary by species. In the new study, researchers studied frogs that carry epibatidine. It’s so potent that just a few millionths of a gram can kill a mouse.
Previous studies have looked at how poisonous frogs became resistant to the toxins they carry. They found that the frogs’ bodies alter the proteins that these toxins bind to. That binding is necessary for the toxin to do its harm. Switching out certain of the protein’s building blocks — or amino acids — changes the shape of that protein. This can prevent toxins from latching onto the protein. But that change, notes Rebecca Tarvin, could have unintended side effects. Tarvin is an evolutionary biologist who worked on this project at the University of Texas at Austin.
Acetylcholine (Ah-SEE-tul-KO-leen) is a chemical messenger important for normal brain function. It works by binding to certain proteins in the brain. Epibatidine binds to the same proteins. And the change that the frogs evolved to guard those proteins from the toxic effects of epibatidine should prevent them from responding correctly to acetylcholine. But it didn’t. To find out why, Tarvin and her colleagues focused on the amino acids that the frogs’ bodies used to build those brain proteins. Such proteins are known as acetylcholine receptors.
The amino acid recipe of those receptors differed between poison frog species that are resistant to epibatidine and close relatives that aren’t.
To see which change mattered most, they worked with the gene from humans that make that receptor. (Humans aren’t resistant to epibatidine.) They put those genes into frog eggs. Then they modified those genes. This involved replacing select amino acids in the human code with substitutions found in poison frogs. That let them home in on a single amino-acid change that protected the receptor from epibatidine.
But that one change wasn’t the end of it, it turned out. “We noticed that replacing one of those amino acids in the human [protein] made it resistant to epibatidine,” explains Cecilia Borghese. She’s a neuropharmacologist at the University of Texas who worked on the project. That change affected how the receptor protein interacted with acetylcholine. Both the toxin and the brain’s messenger chemical bound to the exact same part of the protein. “It’s a very delicate situation,” she notes. While the amino acid change protected the receptor from the frog’s toxin, it also made it harder for acetylcholine to attach.
That should have prevented the brain messenger chemical from doing its job. Yet the frogs seemed fine.
Further research showed why. The amino-acid recipe for the receptor protein differed elsewhere, too. And those extra changes appear to have compensated for any effects of the anti-toxin changes, the researchers found. The result is a protein that won’t let the toxin bind, yet still responds normally to acetylcholine.
Amino-acid changes needed to protect the frogs from this toxin seem to have evolved three separate times in poison frogs, Tarvin says. Three different lines of the animals are immune to the poison. All of them got that immunity by flipping the same switch. But the extra changes that allowed them to still respond normally to acetylcholine differed in the three groups.
It’s “cool”, Brodie says. “These other switches weren't identical,” he notes, yet achieved the same benefit.
acetylcholine A chemical signal that relays messages between nerve cells and other cells in the body.
amino acids Simple molecules that occur naturally in plant and animal tissues and that are the basic building blocks of proteins.
biology The study of living things. The scientists who study them are known as biologists.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
colleague Someone who works with another; a co-worker or team member.
defense (in biology) A natural protective action taken or chemical response that occurs when a species confront predators or agents that might harm it. (adj. defensive)
diet The foods and liquids ingested by an animal to provide the nutrition it needs to grow and maintain health. (verb) To adopt a specific food-intake plan for the purpose of controlling body weight.
disrupt (n. disruption) To break apart something; interrupt the normal operation of something; or to throw the normal organization (or order) of something into disorder.
egg The unfertilized reproductive cell made by females.
evolutionary An adjective that refers to changes that occur within a species over time as it adapts to its environment. Such evolutionary changes usually reflect genetic variation and natural selection, which leave a new type of organism better suited for its environment than its ancestors. The newer type is not necessarily more “advanced,” just better adapted to the conditions in which it developed.
evolutionary biologist Someone who studies the adaptive processes that have led to the diversity of life on Earth. These scientists can study many different subjects, including the microbiology and genetics of living organisms, how species change to adapt, and the fossil record (to assess how various ancient species are related to each other and to modern-day relatives).
gene (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.
genetic Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.
immunity (adj. immune) The ability of an organism to resist a particular infection or poison by providing cells to remove, kill or disarm the dangerous substance or infectious germ. Or, when used colloquially, it means the ability to avoid some other type of adverse impact (such as firing from a job or being bullied).
molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).
neuropharmacology A field of science that focuses on how chemicals such as medicines, alcohol, tobacco and street drugs alter the function of nerve cells in the brain and elsewhere. Doctors and companies that develop new medicines can use this information to treat patients with problems such as drug abuse, pain, brain disorders and more. People who work in this field are known as neuropharmacologists.
poison dart frog A type of brightly colored frog (there are more than 100 different species of these) that belong to the Dendrobatidae family. They secrete a potent poison into their skin. Their bright coloring warns predators that they would provide a toxic lunch. The skin of at least one species can hold enough poison to kill up to 20,000 mice — or 10 adult men. They get their name from the fact that some hunters in the Amazon once used these poisons on the tips of their darts to immobilize their prey.
predator (adjective: predatory) A creature that preys on other animals for most or all of its food.
protein A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.
receptor (in biology) A molecule in cells that serves as a docking station for another molecule. That second molecule can turn on some special activity by the cell.
side effects Unintended problems or harm caused by a procedure or treatment.
species A group of similar organisms capable of producing offspring that can survive and reproduce.
toxic Poisonous or able to harm or kill cells, tissues or whole organisms. The measure of risk posed by such a poison is its toxicity.
toxin A poison produced by living organisms, such as germs, bees, spiders, poison ivy and snakes.