Plenge Lab
Date posted: February 20, 2015 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Oliver Sacks has terminal cancer. If you have not yet read his heart-warming Op-Ed piece in the New York Times and if you only have five-minutes to spare, then I suggest you read his essay rather than this blog about “experiments of nature” in drug discovery. In his essay, Dr. Sacks concludes with the poignant sentence: “Above all, I have been a sentient being, a thinking animal, on this beautiful planet, and that in itself has been an enormous privilege and adventure.

Why do I start this week’s blog about articles of the week with this reference? I do so because of two additional – and seemingly unrelated – items from this week: (1) a brief Twitter exchange with David Shaywitz, Derek Lowe, and others that “few people at public biopharmas write interesting stuff, vs consultant-and-PR-driven banality”; and (2) an article in the New York Times Magazine about how Twitter posts can get you into trouble with your employer (see here).

So why do I blog, tweet, etc. given the potential risk? I enjoy the public exchange of ideas because, as Dr. Sacks write, that is the essence of our “sentient being”. I enjoy a network of inter-related ideas for which I can create unique connections.…

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Date posted: February 7, 2015 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics

ICYMI – the New England Patriots won the Super Bowl. How they did it was remarkable, and improbable. To introduce this week’s articles on human genetics and drug discovery, I want to focus on the interception of Russell Wilson by Malcolm Butler. If the pass is on-target, Seahawks win. By now you know the story: the pass was off-target, and the Seahawks lost.

[A lot has been said about Pete Carroll’s play call (see FiveThirtyEight.com statistical analysis here), but that is irrelevant for this discussion.]

As in football, on-target vs off-target events are highly relevant in drug discovery. Think about what it takes to develop a drug, and how “drug accuracy” (like passing accuracy) can make-or-break a development program. First, you start with a target. Next, you develop a drug against that target. Then, you test the target in pre-clinical models to make sure it is doing what you think it should do. And finally, you take the drug into humans to see if it has an adequate therapeutic index (i.e., is safe and effective).

All along the way you assess whether the therapeutic molecule is selectively engaging and modulating the desired target, and not acting more promiscuously on other targets in the system.…

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Date posted: February 4, 2015 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Imagine you live in Boston or New York. It is Monday January 26, 2015. You are watching headlines of an impending blizzard, trying to figure out the truth about the weather for the next day. You find that the National Weather Service has a cool online tool – experimental probabilistic snow forecast (see here).   As described in Slate magazine (see here), this tool predicted a 67 percent chance of at least 18 inches in New York City.

Unfortunately, most people interpreted this data that there would be 18 inches of snow, not that there could be (with a certain probability) 18 inches of snow.

It was not until Mother Nature did her experiment that we saw the outcome: not much snow in the Big Apple, more than 2 feet of snow in Boston.

The analogy with human genetics is this: it is possible to forecast the functional consequences of deleterious mutations, but it is not until the experimental snow falls – molecular or cellular experiments revealing the functional consequences of mutations – that the functional consequences are actually known. And without knowing the functional consequences of mutations, it is difficult to determine the association of these mutations with human disease.…

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