There are two ways to do it best. One is to start with an ending and work backward. I did this in Postmarked for Death, which began as a nightmare I had, involving an abandoned missile silo taken over by a madman. Not the usual scenario, either: there was no Hollywood missile, as in the movie “Twilight’s Last Gleaming.” It was just two guys in the dark, each with a gun, listening intently for movement in the utter silence. The advantages to this method is that once you know where you’re going, it’s a journey of discovery to get there. Why are these two guys there? How did they get there—what led to it? Once you know who they are, and have established them vividly, the novel will write itself. Better if each is not a walking cliché (walking dead man) but a fallible, real person with both good and bad in them. They have made wrong decisions in the past, but redemption comes in making the right decision in the end. The second method is not knowing the ending. Again, you have the main character fleshed out. And a firm idea of what his or her dilemma is. In the case of The Methuselah Gene, I knew it was going to be a thriller about Big Pharma: how pharmaceutical drugs are tested and produced, combined with how the science of longevity may produce a drug in the near future to extend life by a decade or more. (Science validated recently in the Ron Howard series Breakthroughs.) With the main character (a bachelor researcher tortured by anxiety) fleshed out, it became a matter of doing research, and interviewing a few scientists in the field of genetic engineering so that the plot idea would be plausible. After that? A blank sheet of paper. No idea what would happen to this character, who he would meet, and how the plot idea would evolve. I simply put him into a situation, and listened to what he might say. As one of my fav actors, James Garner, once put it in his biography: “I don’t act, I react. Give me a reactor over an actor every time. As soon as you look like you’re acting, you’re dead. You’re just chewing the scenery.” That’s the way I did it. I put him in motion, and told it from his point of view. He surprised me. That way, there is no way the reader won’t be surprised too. Just let go.