Reducing Animal Use Through State-Of-The-Art Model Generation

"Reduction remains of great importance, and of all modes of progress it is the one most obviously, immediately, and universally advantageous in terms of efficiency."

-W.M.S. Russell and R.L. Burch1
The concept of the three Rs - replacement, reduction, and refinement--in research animal use were first presented in Russell and Burch's seminal book The Principles of Humane Experimental Technique in 1959,1 and have become highly ingrained in life science research. Replacement and reduction are especially important in more recent times, as the UK's 2014 policy paper encouraging the reduction of animal use focuses public attention on the topic,2 and as tightening budgets require strategic use of limited resources.

One way researchers typically minimize animal use is by taking advantage of statistical techniques to guide study design, using the fewest number of animals that can reach statistically significant results.

What many may not realize is that recent advances in transgenic technologies, as well as tissue and cell engraftment, open new avenues to reducing animal use through humanization. By modifying model systems to use the human version of the gene(s) being studied, or to use engrafted human cells or tissues, the models become better able to recapitulate the human system. In many cases, this means that fewer animals can be used during disease study, and particularly in drug discovery and development.

How humanization can reduce animal use

Let's take a look at drug development for Hepatitis C (HCV). With more than 184 million people worldwide chronically infected and limited antiviral treatments available to the majority of the worlds' population,4 HCV is a tremendous global health burden. Development of antiviral treatments has been stymied by the lack of a small animal model. This means that the search for treatments involves the use of in vitro and cellular models that can only provide limited information about effectiveness in an organism. Yet the need for therapies is so great that drug companies and biotechs have surely sent multiple compounds through non-clinical and pre-clinical studies involving a large number of mice. Trials that have yielded very few FDA-approved compounds.

The good news is that through a series of genetic humanizations, a multi-center effort has developed a mouse model that can support the entire HCV lifecycle.5 By having a more effective way to test efficacy in small animals, drug discovery and development efforts can now more effectively identify useful therapeutics at earlier stages in the discovery effort.

Moving forward

The bottom line is that humanizations--genetic and/or via tissue or cell engraftment--are powerful tools for understanding disease processes. The technology to make these changes is highly robust.

  1. W.M.S. Russell and R.L. Burch. The Principles of Humane Experimental Technique. Methuen, 1959. Chapter 6. Available from:
  2. Working to reduce the use of animals in research. Home Office, Department of Business Innovation and Skills, and the Department of Health, UK. 2014. Available from:
  3. The Three Rs Microsite. Canadian Council on Animal Care.
  4. M. Lemoine and M. Thursz. Hepatitis C, a global issue: access to care and new therapeutic and preventive approaches in resource-constrained areas. Semin Liver Dis. 2014 Feb; 34(1):89-97. PMID 24782262.
  5. M. Dorner, et al. Completion of the entire hepatitis C virus life-cycle in genetically humanized mice. Nature. 2013 Sep 12; 501(7466):237-41. PMCID: PMC3858853.