Inevitably when I post a blog on “human biology” I get a series of comments about the importance of non-human model organisms in drug discovery and development. My position is clear: pick targets based on causal human biology, and then use whatever means necessary to advance a drug discovery program to the clinic.
Very often, non-human model organisms are the “whatever means necessary” to understand mechanism of action. For example, while human genetic studies identified PCSK9 as an important regulator of LDL cholesterol, mouse studies were critical to understand that PCSK9 acts via binding to LDL receptor (LDLR) on the surface of cells (see here). As a consequence, therapeutic antibodies were designed to block circulating PCSK9 from the blood and increase LDLR-mediated removal of circulating LDL (and hopefully to protect from cardiovascular disease).
Moreover, non-human animal models are necessary to understand in vivo pharmacology and safety of therapeutic molecules before advancing into human clinical trials.
Beyond drug discovery, of course, studies from non-human animal models provide fundamental biological insights. Without studies of prokaryotic organisms, for example, we would not have powerful genome-editing tools such as CRISPR-Cas9. Without decades of work on mouse embryonic stem cells, we would not have human induced pluripotent stem cells (iPSCs).
The key point is that non-human animal models should be used to answer specific questions that arise when understanding potential therapeutic targets anchored in causal human biology. In contrast, targets should not be selected based on non-human animal models, without a clear causal link in humans.
[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]
I believe that adhering to these principles will be increasingly important as large amounts of human genetic data become available. In the past week alone, for example, there were announcements and high-profile publications demonstrating how much data will be generated in the coming years. AstraZeneca and Human Longevity Inc., led by Founder and CEO Craig Venter, announced a partnership to sequence 2M genomes over the next 10 years (see here). Eric Topol and colleagues at Scripps published a genetic study in Cell on the healthy elderly, or Wellderly (see here, here). While the study concluded that there is “no major singular contributor to healthy aging”, it is likely that genome sequencing will be performed on healthy individuals in addition to those with disease. And another study in Cell, led by Levi Garraway, performed whole-exome sequencing of colorectal tumors in 619 cases from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) (see here). Relevant to the burgeoning field of immune-oncology, the study found a strong correlation of high neoantigen load with increased lymphocytic infiltration and improved survival.
But while non-human animal models are important, it is also exciting to see new human tools being developed and deployed. Two studies this past week illustrate the power of human iPSCs in dissecting human genetic findings.
In a study published in Science Translational Medicine (see here), scientists from academia and industry generated iPSCs from patients with a rare form of chronic pain, inherited erythromelalgia (IEM). IEM results from mutations in SCN9A gene, which codes for the sodium channel Nav1.7. They demonstrated that patient-derived iPSCs differentiated into sensory neurons emulated the clinical phenotype of neuronal hyperexcitability and aberrant responses to heat stimuli. In a tantalizing clinical trial of 5 IEM patients, they found suggestive evidence that a single dose of a small molecule that inhibits Nav1.7 blocked pain perception.
A second study, published in Nature, described a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression (see here). The study, which focused on the Parkinson’s disease gene SNCA (which encodes alpha-synuclein), combined genome-wide epigenetic information with CRISPR-Cas9 genome editing in human iPSCs differentiated into neurons. As summarized nicely in Figure 4 of the manuscript, they demonstrated that carriers of the Parkinson’s disease protective allele have more efficient binding of brain-specific transcription factors at a distal enhancer, which results in lower expression of SNCA.
So, yes, non-human animal models are important in advancing drug discovery programs to the clinic. However, non-human animal models should be used to answer specific questions that arise when understanding potential therapeutic targets anchored in causal human biology. In contrast, targets should not be selected based on non-human animal models, without a clear causal link in humans.