The Billion-Dollar Molecule - Barry Werth  ## Metadata - Author: **Barry Werth** - Full Title: The Billion-Dollar Molecule - Category: #books ## Highlights - Thus the rationale for structure-based design: to optimize the shapes of drug molecules. “Connecting the dots,” Aldrich liked to call it in a heroic oversimplification that made some of the scientists at the tables wince. In effect, the goal is the very opposite of screening: building the molecules one wants rather than fishing for approximations in nature. ([View Highlight](https://read.readwise.io/read/01jpdtb4ab60d9h451yx1by20m)) ## New highlights added March 15, 2025 at 3:42 PM - Once a drug target is identified, the next task is to solve its structure—to reveal the lock’s inner workings with its tumblers exposed. ([View Highlight](https://read.readwise.io/read/01jpdyy0nma5qzbgz5h34yed20)) - Thus the implication of the Nature papers: that cyclosporine worked like a well-thrown monkey wrench, invading a key part of the assembly and bringing the operation to a halt. No new protein folding meant no new attack cells, which meant no graft rejection or autoimmunity. Boger, like many others, was tantalized by the simplicity. ([View Highlight](https://read.readwise.io/read/01jpdz5ys0jfedggq9am5dr4k7)) - Boger raised these issues only to brush them aside. More than anything, he was a rationalist. He believed ineradicably that no decision was ever wrong. A decision based on incomplete information might be, in his word, “suboptimal,” but it couldn’t be incorrect, not logically. The key was to have the best information possible. Given the data now available—about the protein-folding activity of cyclophilin, about the similarities between cyclosporine and FK-506, about the state of the art of drug design and the people he had assembled to do it, about who else was in the field—Boger was convinced that Vertex had as good a chance as anyone, including Merck, of designing the next great immunosuppressive drug, one that would not only capture the $800-million-a-year transplant market, which cyclosporine now dominated, but open up the autoimmune market as well. ([View Highlight](https://read.readwise.io/read/01jpdzeab8sbct34dhwreaxmx6)) ## New highlights added March 15, 2025 at 4:42 PM - “I felt,” he would write, “like a missile looking for a trajectory.” ([View Highlight](https://read.readwise.io/read/01jpe0sz4d8z490grvtvx1jwm1)) - As a surgeon, Starzl knew nothing about controlling the immune system, but then, hardly anyone did. Indeed, few therapies have begun more blindly than immunosuppression in the years after World War II. With the goal of simply knocking out T cells, the first transplant patients received full-body irradiation. It was like fixing a watch with a hammer; the procedure, similar to being exposed to a nuclear blast, destroyed their immunities entirely. Patients were like the “bubble boy,” who lived in a Houston hospital for twelve years before dying of massive infection within weeks of being released. ([View Highlight](https://read.readwise.io/read/01jpe1f5wax54n3hq43876paqq)) ## New highlights added March 22, 2025 at 11:13 AM - There are in any fingernail of dirt between 50 million and 100 million living organisms, representing 3000 to 4000 species and living in a constant state of chemical war. To ensure their own survival, these microbial colonies develop molecules that are lethal to one another. Thus it was with the sample from the Vidda. Screeners at Sandoz discovered it contained a new molecule, which they named cyclosporine, that was fatal to a broad range of fungi. ([View Highlight](https://read.readwise.io/read/01jpkn1kg9d6qn3581ftvvm32q)) - Borel himself is more sanguine. “I’m afraid the definition of a scientist,” he has said, “is a man who can take frustration without end.” ([View Highlight](https://read.readwise.io/read/01jpkn41abnjw1qb0f5qc2fy8b)) - Cyclosporine more than resuscitated the field of organ grafting. After a decade of failure, suddenly there now was a drug that not only disarmed T cells, but didn’t fatally undermine the rest of the immune system. ([View Highlight](https://read.readwise.io/read/01jpkn4yp6swmcsctfr18b3n2s))