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).…
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.…
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).…
