drug discovery

DNA examined under UV light. Genetic data from extremes in human biology may be illuminating for drug discovery projects. Image credit: Wikimedia Commons

The vast majority of compounds that enter clinical trials fail to make it through. The result: few drugs, plenty of bills. The consensus in drug discovery is that things need to change. Part of the problem is the maze that is human biology. Choosing the “right” drug target is difficult when 1) information is incomplete, 2) causes versus effects are unclear, and 3) animal studies don’t perfectly reflect the workings of us homo sapiens (not to mention many other quandaries).

Amidst this background, there is discussion that success rates may improve if experimenters more often look at nature’s own experimentation first.[1-4] When a segment of the population has a trait that is out of the norm, affecting health for the better or worse, what can we learn if we delve deeper, at the genetic level? Can we apply that knowledge to the benefit of others?

Take a look at low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL, the “bad cholesterol,” was discovered to be a culprit behind atherosclerosis, spurring drug discovery efforts at lowering cholesterol. The widely prescribed statins represent a landmark achievement in the field.

It was thought, then, that perhaps raising HDL, the “good cholesterol” would be beneficial. After all, high levels of HDL are associated with a decreased risk of coronary artery disease. However, in findings that could possibly be filed under “Correlation is not causation,” raising HDL does not clearly affect risk. This, after large and costly clinical trials.

Because the statins aren’t perfect for everybody, drug hunters continue to keep LDL in their sights. One approach examining genetic mechanisms has generated intense excitement. It began with a study of a French family that had terrifyingly high levels of LDL and a history of heart disease.[5] It was found that members of this family carried a mutated form of a gene called PCSK9.

That discovery led to the idea that perhaps other variants of PCSK9 would result in low levels of LDL instead. Further investigation revealed a loss-of-function mutant that meant reduced LDL levels for those who carried one copy of this version of the gene and shockingly low levels when people had two. Antibody inhibitors of the PCSK9 protein have been developed, with encouraging results. Clinical trials are now underway.

In general, genetic studies can be performed without heavy reliance on models and hypotheses. They instead may provide insights of their own about human pathology, which might be relevant for drug discovery. Such information has never been more accessible, thanks to new technologies in DNA sequencing. Many service providers are available to assist with DNA sequencing through Assay Depot.

The unfolding story of PCSK9 draws attention to the potential usefulness of human genetics as an instructive beacon for drug discovery. To be sure, not every study of this kind will live up to lofty expectations, and the downstream effects of a gene will not necessarily be resolved by going after the gene or gene product (just like replacing faulty wiring after a house fire doesn’t repair the damage). Still, it appears that observing nature at its extremes may yield genetic insights that should help bring patients to a happy medium.


1. Kamb, A. et al. 2013. Human genetics as a foundation for innovative drug development. Nat. Biotechnol. 31:975-978.

2. Plenge, R.M. et al. 2013. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12:581-594.

3. http://www.forbes.com/sites/brucebooth/2014/05/08/leveraging-natures-experiments-mitigating-drug-discovery-risks-through-human-genetics/

4. http://www.forbes.com/sites/davidshaywitz/2014/01/22/drug-developers-seek-extreme-clinical-phenotypes-to-ignite-medical-discovery/2/

5. http://www.nytimes.com/2013/07/10/health/rare-mutation-prompts-race-for-cholesterol-drug.html?pagewanted=all&_r=0