Plenge Lab
Date posted: August 12, 2016 | Author: | No Comments »

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I recently listened to a TED Radio Hour podcast on failure (link here). Casey Gerald reminded listeners that while his biographical narrative is impressive (here), there have been many failures along the way.

This got me thinking…why don’t more people write their personal biographies in such a way that highlights their successes and failures? I have not seen one, and LinkedIn certainly does not encourage us to log our failures publicly. (Maybe an entrepreneur should start a site called LinkedOut, where you endorse people for failures and bios must be written with failures included!)

So I thought I would give it a try.

I will start with my conventional “success” bio (which can also be found here) to provide context. Then, I will provide my new “failure” bio (also here). At the end, I provide a brief “lessons learned” on how failures have shaped my professional life.  I conclude with a shout out to Charles Darwin, one of history’s most famous observer of failure in nature.

[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.]

Here is my conventional “successful” professional biography.

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If you could pick three innovations that would revolutionize drug discovery in the next 10-20 years, what would they be?

I found myself thinking about this question during a recent family vacation to Italy. I was visiting the Galileo Museum, marveling at the state of knowledge during the 1400-1600’s. The debate over planetary orbits seem so obvious now, but the disagreement between church and science led to Galileo’s imprisonment in 1633.

So what is it today that will seem so obvious to our children and grandchildren…and generations beyond? Let me offer a few ideas related to drug discovery, and hope that others will add their own. I am not sure if my ideas are grounded in reality, but that is part of the fun of the game. In addition, “The best way to predict the future is to invent it.”

To start, let me remind readers of this blog that I believe that the three major challenges to efficient drug discovery are picking the right targets, developing the right biomarkers to enable proof-of-concept (POC) studies, and testing therapeutic hypotheses in humans as quickly and safely as possible. Thus, the future needs to address these three challenges.

1.

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The primary purpose of this blog is to recruit clinical scientists into our new Translational Medicine department at Merck (job postings at the end). However, I hope that the content goes beyond a marketing trick and provides substance as to why translational medicine is crucial in drug discovery and development. Moreover, I have embedded recent examples of translational medicine in action, so read on!

[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.]

There is a strong need to recruit clinical scientists into an ecosystem to develop innovative therapies that make a genuine difference in patients. This ecosystem requires those willing to toil away at fundamental biological problems; those committed to converting biological observations into testable therapeutic hypotheses in humans; and those who develop therapies and gain approval from regulatory agencies throughout the world.   The first step is largely done in academic settings, and the other two steps largely done in the biopharmaceutical industry…although I am sure there are many who would disagree with this gross generalization!

The term “Translational Medicine” has been broadly used to describe the second step, thereby bridging the Valley of Death between the first and third steps.…

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There was an eruption in Iceland last week. No, this was not another volcanic eruption. Rather, there was a seismic release of human genetic data that provides a glimpse into the future of drug discovery. The studies were published in Nature Genetics (the issue’s Table of Contents can be found here), with insightful commentary from Carl Zimmer / New York Times (here), Matthew Herper / Forbes (here), and others (here, here).

[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.]

As I have commented before, human genetics represent a very powerful approach to identify new drug targets (see here, here). I have articulated a 4-step process (see slide #5 from this deck): (1) select a phenotype that is relevant for drug discovery; (2) identify a series of genetic variants (or “alleles”) that is associated with the phenotype; (3) assess the biological function of phenotype-associated alleles; and (4) determine if those same alleles are associated with other phenotypes that may be considered adverse drug events.

There is an important assumption about this model: genes with an “allelic series” will be identified from large-scale genetic studies, and these phenotype-associated alleles will serve as an estimate of function-phenotype dose-response curves.…

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I read with interest a recent publication by Khandpur et al in Science Translational Medicine on NETosis in the pathogenesis of rheumatoid arthritis (download PDF here).  It made me think about “cause vs consequence” in scientific discovery.  That is, how does one determine whether a biological process observed in patients with active disease is a cause of disease rather than a consequence of disease?

In reading the article, I learned about how neutrophils cause tissue damage and promote autoimmunity through the aberrant formation of neutrophil extracellular traps (NETs).  Released via a novel form of cell death called NETosis, NETs consist of a chromatin meshwork decorated with antimicrobial peptides typically present in neutrophil granules.  (Read more about NETs on Wikipedia here.) 

Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in non-experimental studies (read more here).  It is a powerful to determine if an observation in patients is causal.  For example, if autoantibodies are pathogenic in RA, then DNA variants that influence the formation of autoantibodies should also be associated with risk of RA.  This is indeed the case, as exemplified by variants in a gene, PADI4, the codes for an enzyme involved in peptide citrullination (see here). …

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