What Mad Pursuit by Francis Crick

as zero) were omitted and only the positive ones plotted.
    I received another lesson when Perutz described his results to a small group of X-ray crystallographers from different parts of Britain assembled in the Cavendish. After his presentation, Bernal rose to comment on it. I regarded Bernal as a genius. For some reason I had acquired the idea that all geniuses behaved badly. I was therefore surprised to hear him praise Perutz in the most genial way for his courage in undertaking such a difficult and, at that time, unprecedented task and for his thoroughness and persistence in carrying it through. Only then did Bernal venture to express, in the nicest possible way, some reservations he had about the Patterson method and this example of it in particular. I learned that if you have something critical to say about a piece of scientific work, it is better to say it firmly but nicely and to preface it with praise of any good aspects of it. I only wish I had always stuck to this useful rule. Unfortunately I have sometimes been carried away by my impatience and expressed myself too briskly and in too devastating a manner.
    It was at such a seminar that I gave my first crystallographic talk. Although I was over thirty it was only the second research seminar I had ever given, the first having been about moving magnetic particles in cytoplasm. I made the usual beginner’s mistake of trying to get too much into the allotted twenty minutes and was disconcerted to see, after I was about halfway through, that Bernal was fidgeting and only half paying attention. Only later did I learn that he was worrying about where his slides were for the talk he was to give following mine.
    All this was of little consequence compared to the subject of my talk, which, broadly speaking, was that they were all wasting their time and that, according to my analysis, almost all the methods they were pursuing had no chance of success. I went through each method in turn, including the Patterson, and tried to demonstrate that all but one was quite hopeless. The exception was the so-called method of isomorphous replacement, which I had calculated had some prospect of success, provided it could be done chemically.
    As I mentioned earlier, X-ray diffraction data normally gives us only half the information we need to reconstruct the three-dimensional picture of the electron density of a crystal. We need this three-dimensional picture to help us locate the many thousands of atoms in the crystal. Is there any means of obtaining the missing part of the data? It turns out there is. Suppose a very heavy atom, such as mercury, can be added to the crystal at the same spot on every one of the protein molecules it contains. Suppose this addition does not disturb the packing together of the protein molecules but only displaces an odd water molecule or two. We can then obtain two different X-ray patterns: one without the mercury there, and one with it. By studying the differences between the two patterns we can, with luck, locate where the mercury atoms lie in the crystal [strictly, in the unit cell]. Having found these positions, we can obtain some of the missing information by seeing, for each X-ray spot, whether the mercury has made that spot weaker or stronger.
    This is the so-called method of isomorphous replacement. “Replacement,” because we have replaced a light atom or molecule, such as water, with a heavy atom, such as mercury, which diffracts the X rays more strongly. “Isomorphous,” because the two protein crystals—one with the mercury and one without—should have the same form [for the unit cell]. In a loose way, we can think of the added heavy atom as representing a locatable marker to help us find our way among all the other atoms there. It turns out that we usually need at least two different isomorphous replacements to allow us to retrieve most of the missing information, and preferably three or more.
    This well-known method had already been used