Scientists are on a constant quest for knowledge and often use models to help answer scientific questions. Biological models, simplified systems used to study biological processes, are used on the premise that the information obtained from them can be applied to other organisms, like humans. As you know, a number of animal models have been developed over the years in an effort to learn about human disease. One of the strongest arguments in favor of using animal models has been that universal biological principles span the animal kingdom, which they do. However, one very important consideration that limits the value of animal models is the differences that distinguish one species from another. And the differences are vast –ranging from the differences in sequence and expression of DNA, to more gross anatomical and physiological differences.
Time and time again, we see that information learned from animal models has failed to predict what actually happens in people. And which people would animal models predict for anyway? As our biological knowledge grows, we have come to appreciate not only the differences that distinguish one species from another, but also the differences between individuals within that species. Animal models do not address the role that genetic differences between humans play in drug testing or in the study of disease. While there are limitations with all models, there are inherent issues with animal models, including differences in size and physiology from humans, genetic differences, and variations in biological targets that limit the ability of data collected from an animal model to be translated to people. Although a long-standing practice, overreliance on costly and time-consuming animal models has failed to provide relevant answers to today’s scientific questions, giving us hope in many treatments that have only failed in clinical trials, and may have led to the abandonment of drugs that could have been effective for some people.
The scientific community has recognized that there is need for improvement and that more reliable and effective models can be developed with more human relevance. The use of human cells and tissues in combination with sophisticated computer models constructed from human data have greater potential to improve human health and well-being more than animal models ever could. One of the most prestigious scientists of our time, Dr. Francis Collins, Director of the National Institutes of Health, recently stated that transitioning to models which rely on human tissues and stem cells, combined with improvements in assay validation, may make it “justifiable to skip the animal model assessment of efficacy altogether.” (Collins 2011)
Although it will continue to be an uphill battle challenging the tradition of the animal model, in addition to the challenges that come with developing alternative methodologies and getting regulatory agencies comfortable with new testing methods, the opportunity to develop more predictive models without harming animals has never been better. The following section describes some of the latest advancements in research models which hold the promise of being more predictive than animal models because they have more direct relevance to humans from the start.
3 dimensional (3D) cell culture
While much information can be learned from traditional 2 dimensional (2D) cell culture studies in which the cells grow in a single flat layer, one criticism of 2D cultures is that they are too simplistic because they do not reproduce the architecture and the anatomy and physiology of tissues in the body. In vivo, cells communicate with one another and with their surrounding environment, and they respond to mechanical cues. These are parameters that are missed in 2D cultures, but scientists are finding ways to recreate some of the complexity seen in vivo. Advances have been made in cell culture techniques that have introduced a third dimension, enabling cells to organize in ways that are not possible with traditional 2D cell culture. One way to encourage cells to grow in 3D is to provide scaffolding for them. Another way to increase complexity is by introducing more than one cell type, something scientists call a “co-culture.” This allows different cell types to communicate with each other in ways that more closely mimic what happens in the body. Research has shown that when cells are grown in 3D, they more closely mimic the in vivo architecture of tissues and organs which allows the cells to function more like they would in the body.
One branch of 3D cell culture encompasses the building of miniature, complex models of human organs. These “mini-organ” models, also known as “organ-on-a-chip,” are constructed using living human cells on a modified microchip. 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. These “mini-organs” are grown on flexible platforms that enable cells to change shape and respond to physical cues like living organs. Channels are also present to allow fluids to flow between the cells so that nutrients can be distributed. 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, potentially reducing the need for animal testing in other areas of research as well.
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 3D 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.
Advances in simulation technology are facilitating the development of complex and sophisticated models of biological systems. Simulation refers to using computational models to predict the outcome of events. 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. Therefore, 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. The National Science Foundation sees great promise in the power of computer simulation and believes it is central to the advances that will be made in biomedicine in the 21st century.
There are many uses and benefits for using simulations in medicine.
- Simulations can improve surgery by allowing doctors to observe in real time the effect that specific procedures would have by combining simulation tools and imaging techniques.
- Simulators can be programmed with anatomic and physiologic data that is patient specific so that physicians can more accurately design procedures and predict the outcome of specific treatments.
- Simulation could also enable manufacturers to predict how their medical devices work in virtual patients prior to actual patient clinical trials. This could potentially improve the safety and efficacy of medical devices and reduce the cost and time it takes to bring these devices to market. This could overcome the limitations of animal testing procedures which are currently used before human trials, as animal models do not accurately represent variations in human anatomy and physiology.
- A powerful simulation of the human brain is being developed in what is known as the “Human Brain Project.” This digital model of the human brain is being constructed from existing scientific data and continually refined by new data as it is collected. Experts on the subject believe this simulator will offer advantages over animal models because “[Scientists] will be able to repeat the experiment under as many different conditions as they like, using the same model, thus ensuring a thoroughness that is not obtainable in animals.
Modification of clinical trial design
Although scientists rely heavily on animal testing in the drug discovery and development process, there is a more direct and human-relevant way to collect this data that can be used to optimize drug composition and dosing. This can be done with “phase zero” clinical trials, also known as microdosing. In phase zero trials, a very small number of human volunteers, just one or two people, would receive a very low amount of a new drug. 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 and not intended to have a pharmacologic effect, 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.
References: Collins, F.S. “Reengineering Translational Science: The Time Is Right.” Science Translational Medicine. July 2011. Vol. 3, Issue 90. p 1-6.
Food and Drug Administration Website
Huh, et al. “From 3D cell culture to organs-on-chips.” Trends in Cell Biology, December 2011. Vol 21, No. 12. p. 745-754.
Microdosing and the 3Rs
National Science Foundation (NSF) Blue Ribbon Panel (2006). Report on Simulation-Based Engineering Science: Revolutionizing Engineering Science through Simulation. NSF Press.
Scientific American Website.
Wyss Institute Biomimetic Microsystems Website