Two-way Genomic Screens

One of the key problems impeding progress with treating human disorders is that humans are not an appropriate basic research organism. We should not be subjecting patients to candidate pharmaceuticals or therapies without the best possible evidence that these treatments are at least safe, if not efficacious.

For this reason, much biomedical research on drug candidates is conducted on model organisms: Escherichia coli, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus. With these organisms, we have fewer ethical or practical limits to experimentation.

But the use of model organisms has long raised problems of applying findings obtained with model organisms to human patients. Even rodents, like mice or rats, have differences from humans with respect to key features of their pathophysiology. For example, mice rarely suffer from cardiovascular disease in nature (cardiovascular disease is the number one cause of human mortality in advanced countries), making them a difficult model for research in this area.

On the other hand, mice are far more susceptible to cancer malignancies than are humans. As a result, cancer therapies that are developed for the treatment of cancers in mice often fail to show clinical promise, presumably because patients already have similar endogenous cancer-antagonist mechanisms that are as good as those of the treated mice.

To mitigate this problem, Genescient uses Drosophila in a two-way genomic screen strategy with humans. We first use selection to breed Drosophila for health and reproductive longevity.  We then analyze the enhanced animals’ genomes for their unique enhancements, identifying particular genetic loci with systematically altered sequences or other features. We then check those loci in human genomic screens, looking for evidence that they affect comparable functions or indications for one or more age-related disease. Such a “two-way” genomic screen allows us to readily determine the extent to which model organism research focused on a particular genetic mechanism is likely to have benefits for patients in clinics, prior to the start of intensive research on such genetic mechanisms.

With successful corroboration of a particular gene’s involvement in a function from both the model organism’s genomics and human genomics, we can then do much of our initial R&D with the model system. For example, once we have in vitro evidence that a small molecule interacts with the gene or gene-product of interest, we have sufficient warrant to proceed to in vivo testing with the model organism.

In the model organism, we can test for the specific enhancement that we are interested in. We can also readily test for lifelong safety and other side-effects in appropriate short-lived model organisms.

For more on Genescient’s model animal approach, see:  Matsagas K, Lim DB, Horwitz M, Rizza CL, Mueller LD, et al.  2009.  Long-Term Functional Side-Effects of Stimulants and Sedatives in Drosophila melanogaster. PLoS ONE 4(8): e6578. doi:10.1371/journal.pone.0006578