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Those who defend the use of animals in research contend that nonhuman animals are enough like humans to make them scientifically adequate models of humans, but different enough to make it morally acceptable to experiment on them. In addition to the ethical objections to causing suffering to other sentient species, inherent issues with animal models—including differences from humans in both size and physiology, genetic differences, and variations in biological targets—limit the ability of data collected from an animal model to be translated to people.

Furthermore, when animals are used in studies of human diseases, the artificial way in which the disease is induced in the animal is far removed from the way diseases occur naturally in people, limiting the value of such studies. The validity, usefulness, expense and ethics of scientific experiments that rely upon animal models are increasingly being called into question—not only by animal advocates, but by those in the scientific community—which is why it is essential for researchers to develop and utilize models that better reflect human biology and give us the best chance possible of improving human health and well-being.

The following section describes both traditional and cutting-edge alternatives which hold the promise of reducing, refining and ultimately replacing the use of animals in science.

In vitro cell culture

Cell culture refers to the growth of cells removed from an animal or plant in an appropriate artificial environment containing essential components such as nutrients, growth factors and gases. Cell culture can be used for studies of normal cell function, in drug screening and development, and for the production of biological compounds such as therapeutic proteins. Cells in culture are easier to molecularly manipulate, faster, cheaper and more reproducible than animal models. Importantly, human cells can be studied in vitro and offer the potential of reducing animal use in several areas of study.

Many different kinds of cells are available to use in research, including established cell lines and stem cells. Because stem cells have the ability to differentiate into many different types of cells, researchers are excited about their use as research models. Induced pluripotent stems cells (iPSCs) are becoming a very valuable tool in the lab, as advances in cellular techniques are enabling researchers to collect adult body cells from people, reprogram them to an embryonic stem cell-like state and ultimately differentiate the cells to a cell type of interest. These cells are already used in drug development and disease modeling. Because they can be derived from patients with different diseases, iPSCs are playing important roles in personalized medicine.

Many studies rely on cells grown on plastic dishes in a flat monolayer, while others attempt to study cells in three dimensions to better mimic the in vivo scenario.

“Organoids”

Advancements in stem cell biology have facilitated the generation of complex models called “organoids,” miniature in vitro organs which mimic some of the structure and function of real organs. These models form when cells self-assemble and organize into complex 3-D structures. Organoids can be used as disease models, in toxicology and drug discovery studies, and in studies of organ development, among other areas of research. Many organoids have already been generated, including the kidney, liver, heart and lung.

“Organs-on-chips”

Other models developed to simulate tissue and organ-level functionality are “organs-on-chips,” microfluidic cell culture devices with channels lined by living cells. They are designed to mimic the multicellular architecture and biochemical and mechanical microenvironment seen in vivo. These “mini-organs” contain cells grown on flexible platforms that enable them to change shape and respond to physical cues in ways not possible with traditional 2-D or 3-D cultures. Such tools can help researchers better understand the genetic, biochemical and metabolic activities of cells in the context of functional tissues and organs.

A number of microengineered organ models have already been generated and continue to be optimized, including models of the liver, lung, kidney, gut, bone, breast, eye and brain. The hope is that such microsystems, developed with human cells, can replace costly and poorly-predictive animal tests, making the process of drug development and toxicology testing more accurate and human-relevant. These models could be designed to mimic specific disease states and to study tissue development and organ physiology, potentially reducing the need for animal testing in these and other areas of research.

“Human-on-a-Chip”

The Food and Drug Administration (FDA) recently collaborated with the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH) to work on a project called Human-on-a-Chip. Building on the approach described above for individual organs-on-a-chip, the goal of the human-on-a-chip is to generate a miniature 3-D model which includes 10 different human mini-organs linked together to form a physiological system. Because these individual organs would be linked together and would function as a whole system, the human-on-a-chip would be more likely to mimic the activities and biological processes of the human body. While this new tool has the ability to revolutionize toxicology testing, it can also be modified in ways that would facilitate the studying of different disease states. The hope is that this tool, because of its complexity and human-relevance, will be able replace or reduce the number of animals involved in experimentation.

First attempts to connect different organs together on the same chip have already been made. While challenges lie ahead, the current models have provided a strong proof of concept that functional interactions between different organs can be analyzed in these devices.

Computer simulation

Advances in simulation technology are facilitating the development of complex and sophisticated models of biological systems. In addition to modeling occurrences in science that we already understand and have collected data for, simulators advance our understanding by allowing us to test new ideas and try different experimental conditions. Simulation can serve as an alternative to traditional experimental science and has the added perk that experiments that might be impractical or too expensive to perform traditionally can be done using simulation technology.

Autopsy studies and study of postmortem specimens

Autopsies are medical procedures performed by doctors in which an individual’s body is thoroughly examined after death. In addition to acquiring information about the cause and manner of an individual’s death, a great deal of information about disease and injury can also be collected. During the procedure, doctors can determine the cause of an individual’s death, learn how a disease progresses and whether specific treatments for diseases have been effective and collect specimens of tissues and body fluids for additional study.

Epidemiological studies

Epidemiology is a field of research focused on the study of the incidence, distribution and control of disease in a population, enabling scientists to best understand how, when and where diseases occur. Epidemiologists play an important role in advancing science and improving human health and well-being because their investigations into the causes of disease and other human health issues can prevent the spreading of disease and stop the public health issues from happening again. One of the important jobs of an epidemiologist is to try to determine risk factors (e.g. environmental and lifestyle factors) associated with disease as well as factors that may help protect against disease.

Epidemiological studies have demonstrated the relationship between smoking and cancer and have unveiled the association between chemical exposure and disease in the occupational sector. Although epidemiological studies do not prove that specific risk factors actually cause the disease under investigation, they do show the correlation of specific risk factors with incidence of disease.

Noninvasive imaging

Use of medical technologies that provide images of the body, including magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound, have greatly increased our understanding of how the body works and play an important role in diagnostic medicine. Use of these techniques can serve as a replacement alternative, as meaningful data can be derived directly from patient populations.

Although NAVS believes that the overall goal of the 3Rs is replacement of animal use, imaging techniques can also play an important role in the reduction and refinement of animal use in experimentation. For example, if looking at disease progression in an animal model, researchers may sacrifice animals every week to collect data. But if imaging is used instead, they can perform serial studies on the same animal and monitor animals over the course of their lifetimes, significantly reducing the number of animals used. Imaging can also serve as a refinement alternative, enabling fewer invasive procedures to be performed.

Microdosing

“Phase zero” clinical trials, also known as microdosing, are an approach that can reduce the number of drugs going through safety and toxicology testing in animals, which would reduce the number of animals used in testing.

In phase zero trials, a very small number of human volunteers, one or two people, would receive a very low amount of a new drug, a dose so low that it will not produce a pharmacologic effect or adverse reaction. From these studies, the fate of the compound in the human body, including information on how the body absorbs, distributes and metabolizes the drug, can be determined. Because the microdose of the new compound is so low, the risk to the human volunteer is very small. This kind of testing paradigm holds great potential for substantially reducing the number of animals used in safety, pharmacologic and toxicity studies of new compounds, because if a new compound does not have a desired effect in humans, then the compound would not have to undergo additional safety studies in animals.