Plenge Lab

As readers of my blog know, I am a strong supporter of a disciplined R&D model that focuses on: picking targets based on causal human biology (e.g., genetics); developing molecules that therapeutically recapitulate causal human biology; deploying pharmacodynamic biomarkers that also recapitulate causal human biology; and conducting small clinical proof-of-concept studies to quickly test therapeutic hypotheses (see Figure below).  As such, I am constantly on the look-out for literature or news reports to support / refute this model.  Each week, I cryptically tweet these reports, and occasionally – like this week – I have the time and energy to write-up the reports in a coherent framework.

Of course, this model is not so easy to follow in the real-world as has been pointed out nicely by Derek Lowe and others (see here).  A nice blog this week by Keith Robison (Warp Drive Bio) highlights why drug R&D is so hard.

Here are the studies or news reports from this week that support this model. 

(1) Picking targets based on causal human biology:  I am a proponent of an “allelic series” model for target identification.  Here are a couple of published reports that fit with this model.

Read full article...

Date posted: October 5, 2016 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

I have many fears, both professional and personal. When I decided to leave academics for a job in industry in 2013, my biggest fear about making the transition was scientific. In my mind, I had a model of how human genetics might transform drug discovery and development. There were anecdotes (e.g., PCSK9 inhibitors) and a few systematic studies in specific diseases (e.g., genetics of rheumatoid arthritis), but there were many holes to the model. Over the last couple of years, additional anecdotes and systematic analyses have emerged (e.g., Matt Nelson, et al. Nature Genetics), which helps to soothe my fears…but I still have concerns.

[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 blogged about previously, I see two primary routes to go from human genetics to new drug discovery programs (see here, here). The first requires that there are genes with a series of disease-associated alleles with a range of biological effects, ideally from gain- to loss-of-function (allelic series model). The second requires disease-associated genes to aggregate within specific biological pathways, which can then be turned into assays for disease-relevant pathway-based screens such as phenotypic screens.…

Read full article...

Date posted: February 13, 2016 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics Precision Medicine

A study published last week in Science described a large-scale genetic association study of Neandertal-derived alleles with clinical phenotypes from electronic health records (EHRs). Here, I focus less on the Neandertal aspect of the study – which to me is really just a gimmick and not medically relevant – and more on the ability to use EHR data for unbiased association studies against a large number of clinical traits captured in real-world datasets. I also provide some thoughts on how this same approach could be used for drug discovery.

[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.]

The study used clinical data from the Electronic Medical Records and Genomics (eMERGE) Network, a consortium that unites EHR systems linked to patient genetic data from nine sites across the United States. The clinical data was primarily from ICD9 billing codes, an imperfect but decent way to capture clinical data from EHRs. In total, a set of 28,416 adults of European ancestry from across the eMERGE sites had both genotype data and sufficient EHR data to define clinical phenotypes (n=13,686 in the Discovery set; n=14,730 in the replication set).…

Read full article...

Date posted: January 19, 2015 | Author: | No Comments »

Categories: Human Genetics

Recently I was asked by the American Society of Human Genetics (ASHG) to provide my perspective on career and professional development in genetics (see here). At about the same time, I read the book “How Google Works”, by Google Executive Chairman and ex-CEO Eric Schmidt and former SVP of Products Jonathan Rosenberg. A very creative slide deck accompanies the book, which is definitely worth a few minutes of your time (here).

Both got me thinking about opportunities in the pharmaceutical industry for genetic graduate students. Here are a few thoughts based on the outline from the Google slide deck.

What is different now?

In human genetics, large-scale genotyping and sequencing is unlocking the inherited basis of most complex and rare traits in the ideal model organism, humans. This is very different than it was just a few years ago. But there is more: this is happening at a scale that will not likely stop until most humans on the planet have their genome sequenced. Like the “Internet of things”, there will soon be a “Genomes of things”, in which our genomes will be connected to all sorts of data – electronic health records, wearable technology, portable blood monitoring, etc.…

Read full article...

Date posted: December 19, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

This week’s theme is genes to function for drug screens…with a macabre theme of zombies! As more genes are discovered through GWAS and large-scale sequencing in humans, there is a pressing need to understand function. There are at least two steps: (1) fine-mapping the most likely causal genes and causal variants; and (2) functional interrogation of causal genes and causal variants to move towards a better understanding of causal human biology for drug screens (“from genes to screens”).

Genome-editing represents one very powerful tool, and the latest article from the laboratory of Feng Zhang at the Broad Institute takes genome-editing to a new level (see Genetic Engineering & Biotechnology News commentary here).  They engineer the dead!

Genome-scale gene activation by an engineered CRISPR-Cas9 complex, Nature (December 2014).

Since its introduction in late 2012, the CRISPR-Cas9 gene-editing technology has revolutionized the ways scientists can apply to interrogate gene functions. Using a catalytically inactive Cas9 protein (dead Cas9, dCas9) tethered to an engineered single-guide RNA (sgRNA) molecule, the authors demonstrated the ability to conduct robust gain-of-function genetic screens through programmable, targeted gene activation.

Earlier this year, the laboratories of Stanley Qi, Jonathan Weissman and others \ reported the use of dCas9 conjugated with a transcriptional activator for gene activation (see Cell paper here).…

Read full article...

Date posted: November 12, 2014 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics Precision Medicine

I have come across three reports in the last few days that help me think about the question: How many genomes is enough?  My conclusion – we need a lot!  Here are some thoughts and objective data that support this conclusion.

(1) Clinical sequencing for rare disease – JAMA reported compelling evidence that exome sequencing identified a molecular diagnosis for patients (Editorial here).  One study investigated 2000 consecutive patients who had exome sequencing at one academic medical center over 2 years (here).  Another study investigated 814 consecutive pediatric patients over 2.5 years (here).  Both groups report that ~25% of patients were “solved” by exome sequencing.  All patients had a rare clinical presentation that strongly suggested a genetic etiology.

(2) Inactivating NPC1L1 mutations protect from coronary heart diease – NEJM reported an exome sequencing study in ~22,000 case-control samples to search for coronary heart disease (CHD) genes, with follow-up of a specific inactivating mutation (p.Arg406X in the gene NPC1L1) in ~91,000 case-control samples (here).  The data suggest that naturally occurring mutations that disrupt NPC1L1 function are associated with reduced LDL cholesterol levels and reduced risk of CHD.  The statistics were not overwhelming despite the large sample size (P=0.008, OR=0.47). …

Read full article...

Date posted: August 29, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Uncategorized

In my previous blog series I talked about why genetics is important in drug discovery: human genetics takes you to a target, informs on mechanism of action (MOA) for therapeutic perturbation, provides guidance for pre-clinical assays of target engagement, and facilitates indication selection for clinical trials.

Here, I provide an overview of a new blog series on how genetics influences decision-making during drug discovery.  The key principle: human genetics establishes a disciplined mindset and a firm foundation – anchoring points – for advancing targets through the complicated process of drug discovery.  [For those less familiar with drug discovery, the end of this blog provides a brief primer on the stages of drug discovery.]

I highlight three areas: establishing a balanced portfolio, identifying targets with novel MOA, and creating a framework for objective decision-making.  In subsequent posts, I will focus primarily on how human genetics informs on the latter (decision-making), with blogs pertaining to designing assays for screens and target engagement, utilizing pre-clinical animal models, predicting on-target adverse drug events, and selecting indications for clinical trials.

1. Establish a balanced portfolio

Whether in academic research, a small biotech company (see here) or a large pharmaceutical company (such as Merck, where I work), a balanced portfolio of projects is very important.…

Read full article...

Date posted: August 18, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

A key learning from my time in academia was the value of collaborations. Much of my most enjoyable and productive research was conducted in collaboration with fellow scientists across the globe.

I am pleased to report that industry is no different.  After one year working for Merck, I have found that in addition to collaborations across the company ties with external scientific experts focused on advancing programs of interest are actively encouraged.

It is heartening to see how some recent progress in several notable drug development programs is leading to increased excitement around the application of human genetics in identifying human drug targets. As I have previously noted, human genetics can also provide insights to identifying pathways enriched for approved drugs (see Nature article here), which indicates that novel pathways may provide an important foundation for novel drug discovery programs.  Indeed, the use of pathway-based approaches, including phenotypic screens, can provide a powerful way to make complex genetic pathways actionable for drug discovery.

Today, I am excited to note that Merck has launched a Merck Innovation Network (MINt) Request for Proposals to identify collaborations with academic scientists to evaluate genetic targets or genetic pathways for their potential to become drug discovery programs. …

Read full article...