In this post I will build on previous blogs (here, here, here) about genetics for target ID and validation (TIDVAL). Here, I argue that new targets with unambiguous promotable advantage will emerge from studies that focus on genetic pathways rather than single genes.
This is not meant to contradict my previous post about the importance of genetic studies of single genes to identify new targets. However, there are important assumptions about the single gene “allelic series” approach that remain unknown, which ultimately may limit its application. In particular, how many genes exist in the human genome have a series of disease-associated alleles? There are enough examples today to keep biopharma busy. Moreover, I am quite confident that with deep sequencing in extremely large sample sizes (>100,000 patients) such genes will be discovered (see PNAS article by Eric Lander here). Given the explosion of efforts such as Genomics England, Sequencing Initiative Suomi (SISu) in Finland, Geisinger Health Systems, and Accelerating Medicines Partnership, I am sure that more detailed genotype-phenotype maps will be generated in the near future.
[Note: Sisu is a Finnish word meaning determination, bravery, and resilience; it is about taking action against the odds and displaying courage and resoluteness in the face of adversity. …
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. …
Question: What can we learn from Sputnik (see here), DARPA (see here) and disruptive innovation (see here) to invent new drugs?
Answer: The best way to prevent surprise is to create it. And if you don’t create the surprise, someone else will. (This is a cryptic answer, I know, but I hope the answer will become clearer by the end of the blog.)
My previous blogs highlighted (1) the pressing need to match an innovative R&D culture with an innovative R&D strategy rooted in basic science (see here), and (2) the importance of phenotype in target ID and validation (TIDVAL) efforts anchored in human genetics (see here). Now, I want to flesh out more of the scientific strategy around human genetics – with a focus on single genes and single drug targets.
To start, I want to frame the problem using an unexpected source of innovation: the US government.
There is an interesting article in Harvard Business Review on DARPA and “Pasteur’s Quadrant” – use-inspired, basic-science research (see here and here). This theme is critically important for drug discovery, as the biopharma industry has a profound responsibility to identify new targets with increased probability-of-success and unambiguous promotable advantage (see here). …
1.The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
2. An individual or group of organisms exhibiting a particular phenotype.
There are many different phenotypes: strength in the face of adversity (see here); self-reflection in a time of uncertainty (see here); and creativity amidst a sea of sameness (see here).
Phenotypes also refer to disease states such as risk of disease, response to therapy, a quantitative biomarker of medical relevance, or a physical trait such as height (as in the figure above).
For drug discovery, I have put forth the premise that human genetics is a useful tool to uncover novel drug targets that are likely to have unambiguous promotable advantage (see here). The starting point in a genetic study is to pick the right phenotype, one that is an appropriate surrogate for drug efficacy.
And phenotype matters!
Two illustrative examples are the autoimmune diseases type 1 diabetes and rheumatoid arthritis. In type 1 diabetes the immune system destroys the pancreas, thereby preventing insulin secretion and the control of blood glucose levels.
Human genetics has identified many alleles associated with the risk of type 1 diabetes, nearly all of which act on the immune system (see here). …
I believe that humans represent the ideal model organism for the development of innovative therapies to improve human health. Experiments of nature (e.g., human genetics) and longitudinal observations in patients with disease can differentiate between cause and consequence, and therefore can overcome fundamental challenges of drug development (e.g., target identification, biomarkers of drug efficacy). Using my Twitter account (@rplenge), this blog (www.plengegen.com/blog), and other forms of social media, I provide compelling examples that illustrate key concepts of “humans as the ideal model organism” (#himo) for drug development.
Why do drugs fail (#whydrugsfail)? This simple question is at the center of problems facing the pharmaceutical industry. In short, drugs fail in early development because of unresolved safety signals or lack of biomarkers for target engagement, and drugs fail in late development because of lack of efficacy or excess toxicity. This leads to a costly system for bringing new drugs to market – not because of the successes, but because >95% of drug programs ultimately fail. Without improvements in rates of success in drug development, the sustainability of the pharmaceutical industry as we know it is in trouble (see here). Not surprisingly, much has been written about this topic, including analyses of development strategies (Forbes blog, Drug Baron), company pipelines (Nature Reviews Drug Discovery manuscript from AstraZeneca) and FDA approvals (here and here).…
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.,…
Bill James developed the “Keltner list” to serve as a series of gut-check questions to test a baseball player’s suitability for the Hall of Fame (see here). The list comprises 15 questions designed to aid in the thought process, where each question is designed to be relatively easy to answer. As a subjective method, the Keltner list is not designed to yield an undeniable answer about a player’s worthiness. Says James: “You can’t total up the score and say that everybody who is at eight or above should be in, or anything like that.”
The Keltner list concept has been adapted to address to serve as a common sense assessment of non-baseball events, including political scandals (see here) and rock bands like Devo (see here).
Here, I try out this concept for genetics and drug discovery. That is, I ask a series of question designed to answer the question: “Would a drug against the product of this gene be a useful drug?” I use PCSK9 as one of the best examples (see brief PCSK9 slide deck here). I also used in on our recent study of CD40 in rheumatoid arthritis, published in PLoS Genetics (see here).…
At the Spring PGRN meeting last week, there were a number of interesting talks about the need for new databases to foster genetics research. One talk was from Scott Weiss on Gene Insight (see here). I gave a talk about our “RA Responder” Crowdsourcing Challenge (complete slide deck here). Here are a few general thoughts about the databases we need for genomics research.
(1) Silo’s are so last year
Too often, data from one interesting pharmacogenomic study (e.g., GWAS data on treatment response) are completely separate from another dataset that can be used to interpret the data (e.g., RNA-sequencing). Yes, specialized labs that generated the data can integrate the data for their own analysis. And yes, they can release individual datasets into the public for others to stitch together. But is this really what we need? Somehow, we need to make data available in a manner that is fully integrated and interoperable. One simple example of this is GWAS for autoimmune diseases. Since 2006, a large number of genetic data have been published. Still, there is no single place to go see results for all autoimmune diseases, despite the fact that there is tremendous shared overlap among the genetic basis for these diseases.…
I prepared a lecture for immunology graduate students at Harvard Medical School on clinical features of rheumatoid arthritis (RA) for the G1 IMM302qc class.
This blog post pertains to the Systems Immunology graduate course at Harvard Medical School (Immunology 306qc; see here), which is led by Drs. Christophe Benoist, Nick Haining and Nir Hacohen. My lecture is on the role of human genetics as a tool for understanding the human immune system in health and disease. What follows is an informal description of my lecture. The slide deck for the lecture can be downloaded here. Throughout, I have added key references, with links to the manuscripts and other web-based resources embedded within the blog (and also listed at the end). I highlight five key manuscripts (#1,#2, #3, #4, and #5), which should be reviewed prior to the lecture; the other references, while interesting, are optional.
Overview
It is increasingly clear that humans serve as the best model organism for understanding human health and disease. One reason for this paradigm shift is the lack of fidelity of most animal models to human disease. For systems immunology, the mouse is a powerful model organism to understand fundamental mechanisms of the immune system. However, studies in humans are required to understand how these mechanisms can be translated into new biomarkers and drugs.…
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). …
Genetics can guide the first phase of drug development (identifying drug targets, see here ) as well as late phase clinical trials (e.g., patient segmentation for response/non-responder status, see here ). But is there a convergence between the two areas, or pharmaco-convergence (a term I just made up!)? And are there advantages to a program anchored at both ends in human genetics?
Consider the following two hypothetical examples.
(1) Human genetics identifies loss-of-function (LOF) mutations that protect from disease. The same LOF mutation is associated with an intermediate biomarker, but is not associated with other phenotypes that might be considered adverse drug events. A drug is developed that mimics the effect of the mutation; that is, a drug is developed that inhibits the protein product of the gene. In early mechanistic studies, the drug is shown to influence the intermediate biomarker in a way that is consistent to that predicted by the LOF-protective mutations. Further, because functional studies of the LOF-protective mutations provide insight into relevant biological pathways in humans (e.g., a gene expression signature that correlates with mutation carrier status), additional information is known about genomic signatures of those who carry the LOF-protective mutations (which mimics drug exposure) compared to those who do not carry the LOF-protective mutations (which mimics those who are not exposed to drug).…
