Why animals often ‘stand in’ for people

Researchers study lab mice and other species in the hunt to understand the human body — and what will keep it healthy
Dec 4, 2014 — 8:27 am EST
brown Norway rat

The brown Norway rat, here, is widely used in biomedical experiments, including tests on diabetes, aging and cancer.  Scientists publish the results of roughly 100,000 experiments a year that had used rats or mice to “model” effects in people.

Bill Branson, NIH

You might not think we have much in common with scampering mice or flitting fish. However, beneath their fur or scales, these creatures can bear a striking resemblance to people. Under a microscope, their cells and molecules are so similar to ours that many researchers use these and other animals to understand how the human body works — and to predict our likely responses to possible drugs or poisons.

When mice, fish and other animals are used in medical research, they are called models. Just as a model car resembles a real car, animal models are enough like people that researchers can use them in experiments. For a variety of reasons, researchers often cannot perform such tests on people.

Animal models can help researchers address a slew of questions. Will this cancer drug be safe for Grandma? Can anything prevent the mysterious heart failures that cause sudden death in thousands of young athletes each year? Might that soap ingredient harm us — or fish and insects — after it washes down the drain? Will that flea-killing spray hurt Fido — or the baby who crawls on a treated rug?

lab mouse“When trying to address a chemical’s potential health concern, it’s important to understand how it works,” Isaac Pessah tells Science News for Students. He’s a toxicologist at the University of California, Davis. Several years ago, his lab reported that a common germ-killing agent interferes with the movement of calcium in muscle cells. Pessah and his colleagues didn’t learn this by experimenting on people. Instead, the experts used animal models to show how the chemical — called triclosan — was harmful. In mice, it weakened legs and heart muscle, slowing blood circulation. In fish, it slowed swimming speed.

Triclosan is found in many household products. These products range from toothpastes, shampoos and hand washes to fabrics, kitchen sponges and toys.

Before the research by Pessah’s team, other studies had raised questions about whether this widely used chemical might harm people. However, researchers cannot measure a chemical’s hazards by exposing healthy volunteers to varying doses and then counting how many sicken or die. That would not be ethical, safe or even legal. Those are major reasons scientists turn to animal models.

But there are other reasons, too. By tweaking an animal’s DNA or using other means to inflict changes in their cells and tissues, some organisms can closely model human diseases. This way, researchers can check how well a potential therapy works — or how it might prove harmful — before moving on to test it in people. Animals also can help scientists screen large numbers of chemicals quickly to identify a few that might be beneficial. Many drugs you’d find on a pharmacy shelf were first tested on animals.

Animal models aren’t perfect

Though useful and essential for some kinds of research, animal testing has its limits. “Even if you do high-quality work, there’s still the problem of jumping from one species to another,” says Michael Bracken. He’s an epidemiologist at the Yale School of Public Health in New Haven, Conn. Sometimes chemicals and cells act differently within an animal than they do in people.

This harsh reality occasionally rears its head in clinical trials. These are studies involving people. Such tests come at the final stage of developing a new drug. Here, researchers randomly assign volunteers into groups. Some will receive an experimental drug. Others might get either another existing treatment or a placebo (Pluh-SEE-boh). A placebo is an inactive material. Think of it as a dummy pill that looks just like the experimental drug. Treatments must pass these rigorous tests before regulators will let doctors use a new drug to treat patients.

And with good reason.

woman taking medicine

Consider a 1993 trial of a drug to treat hepatitis B. This viral infection attacks the liver. Each year, hepatitis B kills three-quarters of a million people. In the 1993 tests of an experimental drug, 15 hepatitis patients were treated with the drug. Seven — roughly half — soon died when a severe toxic reaction caused their livers to fail.

The researchers were shocked. The compound had caused no apparent problems in tests on mice, rats, dogs and monkeys.

Later, scientists discovered what went wrong. The tested compound looks and acts like the chemical building blocks of DNA, called nucleosides. Humans produce a special protein that delivers nucleosides across cell membranes. However, this delivery protein does not exist in mice, rats or other animals used in prior studies with the compound. As fate would have it, the compound disables that human transporter protein. This keeps new DNA from forming.

The damage occurred in cells throughout the body, with the liver taking the biggest hit. But this problem would never show up in non-human animals. So the original researchers had no clue the drug could poison people.

Gary Peltz works at the Stanford School of Medicine in Palo Alto, Calif. To prevent similar tragedies with other nucleoside mimics that might be headed for testing in people, Peltz and his colleagues created mice with “human” livers.

Peltz started with a strain of mice that lacks an immune system. That prevents their bodies from attacking — also known as rejecting — tissues from another animal. Then his team used a drug (not the test compound) to kill each mouse’s liver before transplanting human liver cells into their bodies. In time, those human cells would create a new, functioning liver.

Another set of mice got to keep their original — and healthy — livers. Those animals served as the experiment’s control mice. These were the animals against which the new mice with “human” livers would be compared.

After a month on the test compound, the control animals with mouse livers seemed to do fine. However, mice with the “human” livers quickly sickened. “After three days,” Peltz recalls, “the vets called me and said, ‘Your mice are extremely sick. What do you want to do with them?’”

Initially, Peltz’s team tested a very high dose of the drug — much higher than the doses used in the fateful 1993 human trial. So he cut the dose given to the group of animals. But these mice also developed liver damage. Had these mouse models been around two decades ago, they could have highlighted the risk this hepatitis drug posed. And that, Peltz suspects, could have prevented the tragic deaths in that 1993 trial. Peltz and colleagues described their findings in an April 15 study inPLOS Medicine.

Finding drug candidates

Animal models also can help at earlier steps in the creation of new medicines. For instance, scientists need to figure out which chemicals to test. But animal testing is costly and difficult. So researchers want to use only those compounds that might be able to “fix” the diseased cells or molecules that aren’t working correctly. They may have to sift through thousands of molecules for the few candidates that show promise.

zebrafish

Here’s how Jeffrey Saffitz took on the challenge. A cardiac pathologist, he works at the Beth Israel Deaconess Medical Center in Boston, Mass.

Saffitz wanted to find potential drugs to keep the heart’s rhythm from going awry. Such an arrhythmia (Ah-RITH-mee-ah), or altered heart rate, can cause sudden death. In some cases, parents can unknowingly pass down the condition to their children. “It’s not unusual for the disease to go undiscovered in a family until a young, relatively healthy person drops dead,” Saffitz tells Science News for Students.

Mutations are unexpected changes to genes. They may occur by accident. Other times, a disease or pollutant causes them. Scientists had identified mutated genes that could cause the arrhythmia that Saffitz studies.

Based on this knowledge, Saffitz and his colleagues engineered a new strain of zebrafish. A strain is a group of individual organisms belonging to a species that share one or more distinctive characteristics. “The fish are really sick,” says Saffitz. “They have this really big, abnormal heart — and they die.” These zebrafish also contain the same mutation that shows up in people with a rare, severe form of arrhythmia.

The researchers further tweaked the animals’ genetic programming by inserting a firefly gene. This type of manipulation is an example of genetic engineering. The firefly gene contains the directions for a cell to make a protein. That protein emits light when the fish’s heartbeat begins faltering. In this animal model, any chemical given to the fish that dimmed or shut off the “light” might represent a potential drug for treating the arrhythmia.

Speedy and thrifty

You might wonder why the researchers didn’t screen the compounds using mice instead of fish. After all, mice are more similar to people. In a nutshell, it came down to time and cost. Just 24 hours after a fish egg is fertilized, “you have a beating heart,” Saffitz explains. “Within 48 hours, we could already see the heart is sick.” Mice, in contrast, take much longer — three weeks — to be born. Plus, they’re far more expensive to feed, house and rear.

With its zebrafish model, Saffitz’s team tested 5,000 compounds in about six months. Of those, just three looked promising. One had previously entered human testing. Decades ago, that compound went through a trial for bipolar disorder. This brain condition causes shifts in mood and energy levels that make it hard to carry out everyday tasks. The compound “got far enough to be tried in people,” says Saffitz. However, “we haven’t been able to access the data,” he explains. “So we don’t know whether [the drug] turned out to be safe or not.”

Meanwhile, the researchers did the next best thing. They tested the compound in other species. “Just because [the molecule] works in fish doesn’t mean it will work in mammals or people,” Saffitz says. Consider the difference in heart structure. A mammal’s heart has four chambers. Fish hearts have just two. Such structural differences might hint at other differences that could affect heart function.

So, to test the chemical in mammals, the researchers created two models of a different kind. Instead of using whole animals, these models used cells taken from live animals and grown in Petri dishes. In one case, the experts engineered cells from a rat's heart to contain the same mutation as their zebrafish had. The second model instead used cells from a human heart. But they didn’t come directly from the heart. Scientists first took blood from two people with a severe, inherited form of arrhythmia. They then treated those cells, converting them into stem cells. Stems cells can be induced to mature into any other type of cell. Here, the researchers coaxed them into becoming heart-muscle cells.

In both rat and human cells modeling those in the heart, the test chemical seemed helpful. It kept the heart cells from dying. It also corrected specific protein abnormalities found in people with arrhythmia. The researchers reported their results June 11 in the journal Science Translational Medicine.

A long road

guinea pigStill, much work remains before this molecule can ever reach patients. Of the many thousands of compounds tested in cells and in animal models each year, only a few will enter clinical trials. Of those, fewer than one in five makes it through to the final stage to become a drug that doctors can prescribe to treat patients.

As for the arrhythmia compound, “We don’t know exactly what it is doing,” Saffitz says. “We don’t understand the mechanism.”

Currently, his lab is trying to work out how the molecule restores the inner workings of cells to restore normal heartbeat patterns. If things go well, the group might team up with a drug company. Together, they might make tiny changes to the drug’s recipe, boosting its power. They’d also like to test the drug in larger animals and to find which dose of it that might be both safe and effective.

“Those are the steps you go through to take a molecule into humans,” Saffitz explains. 

Luckily, people aren’t the only “guinea pigs” on whom potential medicines or toxic compounds are tested. Sometimes researchers use mice, rats and other organisms (and occasionally real guinea pigs). With the help of genetic engineering, some of these animals can model human diseases for the early phases of drug testing. And though they aren’t perfect replicas, animal models can save countless research hours and dollars by identifying which molecules, among many thousands, are actually worth testing in people.

 

Word Find (click here to enlarge for printing)

wordfind

Power Words

animal model    A nonhuman animal used to stand in for people in research testing. Which animal a lab uses will depend on how closely parts of its body or chemical-signaling systems match those in people.

arrhythmia      An altered, usually erratic pattern in a normal rhythm, such as the pace of an individual’s heartbeats. A persistent, untreated heart arrhythmia can prove very dangerous.

biopolar disorder    A disease that causes unusual shifts in a person’s mood, energy, activity level and interest in carrying out normal daily tasks. The condition is sometimes called manic-depressive illness. Sometimes a person can feel elated and overly energetic. A few days later, the same person may feel depressed and unwilling to leave their house or talk with anyone.

cardiac    Of or relating to the heart.

chemistry  The field of science that deals with the composition, structure and properties of substances and how they interact with one another. Chemists use this knowledge to study unfamiliar substances, to reproduce large quantities of useful substances or to design and create new and useful substances. (about compounds) The term is used to refer to the recipe of a compound, the way it’s produced or some of its properties.

clinical trial    A research trial that involves people.

compound     (often used as a synonym for chemical) A compound is a substance formed from two or more chemical elements united in fixed proportions. For example, water is a compound made of two hydrogen atoms bonded to one oxygen atom. Its chemical symbol is H2O.

control     A part of an experiment where there is no change from normal conditions. The control is essential to scientific experiments. It shows that any new effect is likely due only to the part of the test that a researcher has altered. For example, if scientists were testing different types of fertilizer in a garden, they would want one section of it to remain unfertilized, as the control. Its area would show how plants in this garden grow under normal conditions. And that give scientists something against which they can compare their experimental data.

DNA  (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

engineer  A person who uses science to solve problems. As a verb, to engineer means to design a device, material or process that will solve some problem or unmet need.

epidemiologist   Like health detectives, these researchers figure out what causes a particular illness and how to limit its spread.

ethics   A code of conduct for how people interact with others and their environment. To be ethical, people should treat others fairly, avoid cheating or dishonesty in any form and avoid taking or using more than their fair share of resources (which means, to avoid greed). Ethical behavior also would not put others at risk without alerting people to the dangers beforehand and having them choose to accept the potential risks.

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.

genome    The complete set of genes or genetic material in a cell or an organism.

genetic engineering   The direct manipulation of an organism’s genome. In this process, genes can be removed, disabled so that they no longer function, or added after being taken from other organisms. Genetic engineering can be used to create organisms that produce medicines, or crops that grow better under challenging conditions such as dry weather, hot temperatures or salty soils.

hepatitis   A potentially serious form of liver inflammation due to infection by any of several hepatitis viruses. They have been named hepatitis-A, ‑B, -C, ‑D and ‑E viruses.

immune system  The collection of cells and their responses that help the body fight off infection.

mammal   A warm-blooded animal distinguished by the possession of hair or fur, the secretion of milk by females for feeding the young, and (typically) the bearing of live young.

mechanism  The steps or process by which something happens or “works.” It may be the spring that pops something from one hole into another. It could be the squeezing of the heart muscle that pumps blood throughout the body. It could be the friction (with the road and air) that slows down the speed of a coasting car. Researchers often look for the mechanism behind actions and reactions to understand how something functions.

metabolism  The set of life-sustaining chemical reactions that take place inside cells. These reactions enable organisms to grow, reproduce, move and otherwise respond to their environments.

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).

mutation  Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant. It is said to be mutated.

nucleoside   Natural chemicals that contain a sugar bound to a nitrogen-based material. Examples include cytidine, uridine, adenosine, guanosine, thymidine and inosine. Some are used to treat cancer or viral diseases.

pathologist    Someone who studies disease and how it affects people or other infected organisms.

Petri dish  A shallow, circular dish used to grow bacteria or other microorganisms.

placebo   A substance that has no therapeutic effect, used as a control in testing new drugs.

proteins      Compounds 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. The hemoglobin in blood and the antibodies that attempt to fight infections are among the better known, stand-alone proteins.Medicines frequently work by latching onto proteins.

random  Something that occurs haphazardly or without reason, based on no intention or purpose. (in study design) To assign people in one group or another based on no particular reason; indeed, researchers often use a computer to make the decision without knowing anything about the individual.

RNA  A molecule that helps “read” the genetic information contained in DNA. A cell’s molecular machinery reads DNA to create RNA, and then reads RNA to create proteins.

stem cell  A “blank slate” cell that can give rise to other types of cells in the body. Stem cells play an important role in tissue regeneration and repair.

strain  (in biology) Organisms that belong to the same species that share some small but definable and distinctive characteristics. For example, biologists breed certain strains of mice that may have a particular susceptibility to disease. Certain bacteria may develop one or more mutations that turn them into a strain that is immune to the ordinarily lethal effect of one or more drugs.

tissue   Any of the distinct types of material, comprised of cells, which make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues. And brain tissue will be very different from bone or heart tissue.

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.

toxicology  The branch of science that probes poisons and how they disrupt the health of people and other organisms.

triclosan    A germ-killing chemical added to some common products such as hand soaps and sponges.

NGSS: 

  • MS-LS3-1
  • MS-ETS1-4
  • HS-ETS1-1

Citation

D. Xu et al. Fialuridine induces acute liver failure in chimeric TK-NOG mice: A model for detecting hepatic drug toxicity prior to human testing. PLOS Medicine. April 15, 2014. doi: 10.1371/journal.pmed.1001628

A. Asimaki et al. Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Science Translational Medicine. June 11, 2014. doi: 10.1126/scitranslmed.3008008

B. Djulbegovic, I. Hozo and J.P.A. Ioannidis. Improving the drug development process: more not less randomized trials. Journal of the American Medical Association. Jan. 22-29, 2014. doi:10.1001/jama.2013.283742.

G. Cherednichenko et al. Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle. Proceedings of the National Academy of Sciences. Aug. 28, 2012. doi: 10.1073/pnas.1211314109.

M.M. Schultz, S.E. Bartell and H.L. Schoenfuss. Effects of triclosan and triclocarban, two ubiquitous environmental contaminants, on anatomy, physiology, and behavior of the fathead minnow (Pimephales promelas). Archives of Environmental Contamination and Toxicology. July 2012. doi: 10.1007/s00244-011-9748-x. 

Further Reading

A.P. Stevens. “Explainer: What is a stem cell?Science News for Students. June 27, 2013.

A.P. Stevens. “Stem cells: The secret to change.” Science News for Students. April 10, 2013.

J. Raloff. “Antibacterial agent can weaken muscle.” Science News. Aug. 14, 2012.

J. Raloff. “A new source of dioxins: Clean hands.” Science News. May 18, 2010.

Classroom questions: Why animals often ‘stand in’ for people.