Plenge Lab
Date posted: June 4, 2013 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Precision Medicine


As I sought advice from colleagues about my career, I was frequently asked if I would prefer to work in academics or industry (emphasis on the word “or”).  The standard discussion went something like this:

ACADEMICS – you are your own boss and you are free to chose your own scientific direction; funding is tight, but good science still gets funded by the NIH, foundations and other organizations (including industry); the team unit centers around individuals (graduate students, post-docs, etc), which favors innovative science but sometimes makes large, multi-disciplinary projects challenging; there is long-term stability, including control over where you want to work and live, assuming funding is procured and good ideas continue; your base salary will be less than in industry, but you still make a good living and there are opportunities to consult – and maybe even start your own company – to supplement income.  Bottom line: if you want to do innovative science under your own control, work in academics – as that is where most fundamental discoveries are made.

INDUSTRY – there are more resources, but those resources are not necessarily under your control (depending upon your seniority); the company may change direction quickly, which changes what you are able to work on; while drug development takes 10-plus years, many goals are short-term (several years), which limits long-term investment in projects that are risky and require years to develop; the team unit centers around projects (e.g., making drugs), so there is less individual glory but more opportunities to do multi-disciplinary projects; there is more turn-over in industry, which means you may need to switch jobs (including location – where you want to live) in several years.  Bottom line: if you want to make drugs as part of a team, work in industry – as that is the goal of most pharmaceutical companies.

But as I discussed opportunities with good, smart people from both sides, I realized a fundamental flaw in the way I was approaching the question: it was not about academics “or” industry; rather, it was about what I want to achieve in my scientific career.  For me, the question changed to academics AND industry, as the goals of drug and biomarker discovery are shared by both sides.  As I formulated my vision of where to take the field (in my case – the role of genetics in clinical care), the question became about where I could have a bigger impact, and that this would likely include both academics and industry.  Here is what I mean.

Years ago in graduate school at CWRU, I became passionate about the role of human genetics in clinical medicine.  I wasn’t sure how genetics would have an impact in clinical care, but I could see potential clinical applications (from drug discovery to diagnostic tests and beyond).  I was fortunate to work in a progressive lab, led by Hunt Willard, where a talented group of post-docs (and roommates!) were doing research which ultimately led to a start-up company, Athersys.  During my time as a graduate student, but also throughout my training – medicine residency at UCSF, post-doc at the Broad Institute, faculty member at HMS – I accepted that the best way to bring human genetics to patient care is through commercialization, and that commercialization is best done through a private company.  But the question was always: what was the commercial product, based on human genetics, that could truly improve the lives of patients?

Until recently, I could never easily see the commercial aspects of human genetics – other than the general claim of “personalized medicine”, which always seemed very exciting and promising, but a long way off.  (See above – companies need to meet short-term objectives.)  There were claims by some that the human genome project would magically reveal drug targets, which would reduce attrition rates and make drug discovery efficient and cheap.  I could not easily make that connection, however…which in retrospect could have been for many reasons, including my lack of imagination or lack of understanding of drug discovery.

Now, however, I see something different: human genetics has the ability to find drug targets in a way that could transform the industry.  This is an ambitious statement, I know…especially for someone who has never formally done drug discovery!  I also know that this ideal may seem like a long way off  – and much of it is.  But now there are short-term opportunities (see PCSK9 example – blog post here) on the way to what will certainly be long-term opportunities (genes to pathways to drugs). In fact, I would argue that in 10 years, human genetics will be the dominant strategy to discovery new drugs for complex diseases such as rheumatoid arthritis, heart disease, diabetes, etc.

The argument goes something like this: (1) the major problem in drug discovery is high attrition rates, which leads to high amortized costs for drugs that come to market; (2) the high attrition rates are due to failure in clinical trials (lack of efficacy or excess toxicity); (3) these failures point to the inability of existing pre-clinical models to test “therapeutic hypotheses” – the hypothesis that a target, when perturbed, is safe and effective at the time of target validation; (4) human genetics, through associations of mutations/alleles to clinical phenotypes that are appropriate surrogates for efficacy and toxicity, provides a rigorous test of the therapeutic hypothesis at the time of target validation – I like to think of human genetics as providing estimates of dose-response curves at the time of target validation; (5) there are features of genes – namely genes with a series of alleles with a range of functional perturbations (from gain-of-function to loss-of-function) – that make them attractive drug targets.  

If only we can find such genes.

Here is why I think we will:  (1) There are several compelling anecdotes that provide support for the “allelic series” model, with PCSK9 serving as the poster child. (2) Next-generation sequencing (NGS) technology now makes it possible to sequence the entire genome in extremely large patient populations to find all classes of alleles (from common to rare; from SNPs to indels; coding and non-coding; etc). (3) For most complex diseases, there are a sufficient number of patient samples to do the right large-scale sequencing study, which can be integrated with GWAS in even larger sample collections, to find an allelic series. (4) While NGS costs are dropping, large-scale experiments (hundreds of thousands of individuals – yes, hundreds of thousands) are still beyond the scope of any single lab, institution or company – and will be out-of-scope for many years.  (5) There is a growing consensus among researchers in academics and industry that large, pre-competitive academic-industry collaborations are the best way to build large genetic databases to find genes with an allelic series for drug discovery (see recent announcement of the “Global Alliance” here and here – white paper is here).  

This last point is critical.  A few years ago, we did not know enough about the genetic architecture of complex traits to make this last statement with sufficient conviction.  As a consequence, individual labs, institutions or companies were reluctant to open their data vaults to share genetic data broadly.  Now there is enough empirical genetic data, supported by predictions based on sound population genetic theory, to motivate researchers to collaborate (see blog post here on polygenic architecture of complex traits).  Not all do, but enough thought-leaders are sold on this concept that most researchers in academics and industry are open to pre-competitive collaborations. (See previous blog post here on a related topic of databases.)

Which brings me back to my statement that it is about academics AND industry, not academics OR industry.  For me, in my scientific field of “human genetics of complex traits to improve the lives of patients“, it is not one or the other.  For this model of genetics in drug discovery to succeed, it will need collaboration on both sides. If such pre-competitive collaborations don’t develop, then I believe that the process of using genetics to guide drug discovery will be severely delayed.  Researchers in academics and researchers in industry share the same goals – to improve the lives of patients.  The short-term incentives might be different, but the long-terms goals are the same.  We need innovative, brave, thoughtful researchers on both “sides” to embrace this model, for we cannot do it in isolation.

Thus, for me, it is about the scientific question (genetics as a guide for drug discovery) and the opportunity to test therapeutic hypotheses anchored in human genetics.  And to test these hypotheses to completion – not some intermediate step that leaves me wanting.  I started to ask where I could make the biggest difference to accomplish this vision.  I could then see exciting opportunities in both academics and industry.  This allowed me to make an informed choice not based on the standard discussion of academics or industry, but based on my vision of human genetics.  

Leave a Reply