The Role of Motivation in Scientific Research
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Karle, Jerome
“Socrates was a Greek.He gave people advice.They killed him.” - with this summary by a young scholar, Jerome Karle familiarizes the audience with potential side effects of well-intended advice. Still, despite the cautionary tale of Socrates, the first half of his talk is dedicated to the young researchers present and some general advice on how to be successful as a scientist.If one strives for wealth, power, easy living or even general recognition, science is the wrong profession, Karle says. If one, however, is able to derive pleasure from progress, even without the recognition of others, science might just be the right choice. In any case, the keys to success are motivation, hard work and persistence, Karle explains, not only with respect to scientific challenges, but also to those challenges life and nature pose. While he admits that everyone has to make compromises, he urges the young researchers to avoid “destructive” compromises, i.e. those that affect the foundations of their own motivation. Just one year before the present talk, the chemist Karle had shared the 1985 Nobel Prize in Chemistry with the mathematician Herbert Hauptman. The Laureates had been rewarded "for their outstanding achievements in the development of direct methods for the determination of crystal structures". These methods allow to circumvent the so-called “phase problem” of x-ray crystallography and to determine chemical structures from x-ray diffraction data in very short timespans. Today (2013), x-ray crystallography is routinely employed to elucidate or confirm the structures of unknown molecules, be they synthetic or natural, using merely minute substance quantities {Link to X-ray Topic Cluster}. Still, for Karle himself, the path to success was not always as exciting as it might seem from a today’s perspective. He points out that the translation of the mathematical solution to the phase problem into a technique that could actually be used by x-ray crystallographers took some ten years - and a lot of motivation. Fortunately, motivation for chemical challenges appears to be abundantly available in Karle’s family: his wife, Isabella, and two of his three children are chemists. David_prizes/chemistry/laureates/1985/karle-autobio.html
 Good morning. That's all the German you'll get from me. Sorry. It's very pleasant to be here in Lindau. This is my first visit. I hope it's not my last. My talk this morning is divided roughly into three parts. The first part might be considered advice to young people. I do so with great hesitation. I'm not used to handing out advice, and I'm somewhat apprehensive about doing so. The second part of the talk will, in some sense, be an indication of how the remarks that I initially make apply to my own life experience. And then, since I can't resist talking about science and my own field, there will be some discussion about some applications of crystallographic techniques to chemistry. I would like to start off by illustrating my apprehension concerning advice by telling you a little story. It was a little girl, I suppose, about eight years old, about the third grade, and she had a homework assignment. The members of the class were asked to write a small composition about a famous person in history, and she decided to write about Socrates. She wrote a little composition that went something like this. Socrates was a Greek. He gave people advice. They killed him, and with that apprehension I'll continue. At some time in a person's life, it is worthwhile, if not necessary, to make decisions concerning the path to be followed, that is, the profession that would be most attractive and how it is to be pursued. The earlier that such decisions can be made, the better. Although enough interest and determination, with enough interest and determination, such decisions can often be delayed until adulthood. It is not so important to make a detailed decision. What is important is to decide upon the direction of one's interests so that appropriate education and training can be pursued. I had the good fortune of knowing at an early age that I wanted to be a scientist. I really did not know what kind of a scientist I wanted to be, and it did not seem to be important to make such a decision. By the time I was about nine years old, I was already reading about scientific and technical subjects, and I found that such reading was more interesting than the usual literature devoted to young people. There was little question in my mind that science would occupy my future, and I was committed and determined to make sure that that was the case. It is apparent that a deep interest in a subject or area of activity, and a personal identification and respect for a subject or activity, is a very strong motivation that can carry a person beyond the potential adversities that so often appear to inhibit the achievement of a person's goals. In my case, I obtained an advanced degree in science after many adversities, and artificial barriers were overcome. The barriers were of various types, economic and social, which had nothing to do with the science that held my interest or my competence to pursue it. They nevertheless could have been quite demoralizing, and may very well have discouraged other people under similar circumstances. The economic difficulties took the form of not being able to afford advanced education, and the social barriers concerned quotas and limitations on the support of advanced education. A strong motivation and dedication to the future can overcome impediments and lead to a successful career. It is important to recognize that in order to accomplish almost anything worthwhile, hard work and dedication are required. But if a person is content with his or her choices in life, even if the hard work is not always a joy, it can be satisfying. Satisfaction derives from progress and an occasional accomplishment. Hard work, especially intellectual hard work, for protracted periods is achieved only with motivation, the motivation that derives from commitment to a specific course in life. Numerous examples can be derived from the world of basic science. For example, a deep interest in basic science can motivate people to investigate problems simply for their scientific interest, and not primarily for the recognition that may come from colleagues for solving problems, for the immediate usefulness of solutions, or for potential monetary gain. Purely and simply, it is possible to have such an interest in one's chosen activity that other attractions and pressures are not able to distract a person from his or her true interest in life. Basic science very often ultimately leads to very useful results, but utility as a goal without the aspects of scientific challenge and an appeal to scientific curiosity would not generally be an attractive activity for someone with a strong interest in the pursuit of basic science. Just as there are often barriers to the achievement of an adequate education in the normal course of events, life and nature provide numerous barriers to the achievement of one's goals. To become discouraged instead of staying with one's goals will result, evidently, in the failure to realize one's potential. Again, motivation can play a major role in overcoming adversities. Along with dedication and hard work, it is often necessary to have persistence, sometimes great persistence. My own experience showed this to be true. It was about ten years of hard work and persistence before a general procedure was developed for making practical applications of the foundation mathematics for crystal structure determination for whose development the latest Nobel Prizes in chemistry were awarded. Under development of the foundation mathematics, there were many difficult steps that required testing and discovery. These steps are called by some bridging. In a simple way, I regard bridging as the modification of mathematics so as to be suitable for application to experimental data and modification of the experimental data so that it could be suitable for use with the mathematics. In complicated problems such as the determination of the three-dimensional atomic arrangements in complex structures, bridging can be a rather difficult and tedious area of intellectual activity. This was certainly the case, and it largely accounted for the considerable time between the development of foundation mathematics and the development of general procedures for widespread application of the theory. Structures in the range of about 100 to 400 atoms often present problems that are difficult to overcome. There are therefore still some hard problems remaining in structure determination. In addition, there are indications that improvements can be made in the way the techniques for macromolecular research are carried out. Macromolecules can be described as structures having about 500 or more atoms whose positions need to be determined. Several techniques can be applied to macromolecules that make them easier to solve than some structures having fewer atoms. The motivations that played an important role in bringing structure research to its present state of high competence and reliability also motivate the pursuit of current fourth end problems. I have been implying that it can be very satisfying to be strongly motivated and to set high goals in life. Such an approach may necessarily lead to an easy course through life and may not provide what one personally regards as success. It is important to be satisfied with trying one's best. There are many documented circumstances in which young people set very high goals which they may not ever achieve or at least as soon as they would hope or expect. With the consequence that a lack of self-confidence or great disappointment and this despondency may accrue, such mental states can be dangerous and damaging. It is important to learn how to live with adversity. As life proceeds, almost everyone has to make compromises with the circumstances in which they find themselves. It is easier to accept circumstances that may not be ideal when a person's primary interest in life, the one for which a person has strong motivations, can be pursued. If you are convinced that your goals are worthwhile, stay with them and try not to make destructive compromises. If your primary objectives are matters such as wealth, power, recognition, easy living, a scientific career is probably not a particularly good way to achieve such goals. Such motivations would appear to run counter to a creative scientific career. Naturally, someone may decide from an early age that his or her goal in life is to be wealthy. Many of the personal characteristics that I have described for successful pursuit would still be applicable. Beyond that, I personally have no recommendations for such a career. It is also important to understand that in the course of a person's life, especially in the sciences, it is very rare that high recognition will be achieved. And setting recognition as a primary goal can only serve to interfere with the pursuit of science for its own sake. In my view, the greatest satisfactions come from the act of scientific discovery, and it is a valuable asset to be able to derive great satisfaction from personal participation and discovery, whether or not one's colleagues recognize the value of the work. A large part of success in life comes from having clear goals and the proper outlook. If the proper outlook includes personal satisfaction from personal achievement, it is possible to look forward to a life of joy and a life of accomplishment. That's all the advice I have. I would like to continue with the talk now by discussing my own field of research in the context of motivations that I've had, and also to illustrate, if I may, how one and sort of broad outline, broad brush outline, how one can go from the measurement of the intensities of X-ray scattering to a complete molecular structure. The subject is the three-dimensional structure, atomic arrangements of molecules, as obtained from so-called X-ray diffraction applied to the crystalline state. Through the advent of modern technology such as computers, electronics, instrumentation, and sophisticated computer programming, it has become possible to mount a small single crystal of an unknown substance on an automatic X-ray diffractometer, and with minimal human intervention see the complete geometric arrangement of atoms in the molecule displayed on a video screen. Depending upon the size of the molecule, the process may take as short a time as one day. Automatic structure determination is feasible today for very many small and medium-sized structures, particularly if the crystal contains a center of symmetry. Larger and more complex structures require the special expertise of professional crystallographers. The present ease of structure determination, and even the possibility of deriving a structure from X-ray data, stems from the fundamental theoretical and practical advances made in solving the phase problem. What happens is that a collimated beam of X-rays of a particular wavelength is made to impinge on a single crystal, and that crystal is rotated about various axes, different sets of scattering planes. Acting like a ruled grating, come into position for the X-ray beam to be diffracted. The intensity and the angular orientation of hundreds or thousands of reflections are measured and recorded by an automatic diffractometer, formerly by photographing. The phases associated with the diffracted beam, however, with rare exception, cannot be measured experimentally, and you need the phases as well as the intensities. Let me see if I can get my first slide. This is called a Weisenberg photograph. Each one of the spots comes from a particular plane in the crystal, and its location can determine by a fairly simple geometric calculation what particular plane in the crystal scattered each of the spots. And as you notice, they have varying intensities, some are very light and very difficult to see, others are so black that it's difficult to estimate their intensity. Many years ago, perhaps over 20 by now, this was a general technique for obtaining X-ray diffraction information, and it was necessary to sit for sometimes several months with a comparison strip and make a comparison and estimation of the intensity in each one of these spots. Nowadays, all of this is taken care of for you in automatic instrumentation. I am not going to make a deep mathematical conversation about this business, but this mathematics here, this function, rho, represents the structure of a crystal because it represents the density, electron density, in a crystal. In order to compute this function over here, which is called the Fourier series, you have to know all about these numbers here. These numbers are complex numbers, and that means that there's a magnitude and some kind of an angle associated with them. And here's where the problem resides. Those black spots give you information about this part of the number, and superficially, it appears that they give you no information at all about this angle, which can be called the phase angle, and you need both this magnitude and this angle in order to compute this function. The reason why the electron density in the crystal represents its structure is because atoms are located where electron densities have their greatest value near the peaks of the electron density function. So that if somehow or other you could find this, then it's a trivial calculation in a computing machine to obtain this density function that you wish to have. Well it was decided that since you only get this part and not that part, that there was no chance of directly taking x-ray intensity information in order to make this calculation. And it was actually quite obvious to Herbert Houtman and I that the phase information was actually contained in the intensity information that was measured and seen in the x-ray diffraction photographs. Now it's one thing to know that the answer is there and quite another matter to find the answer. And so it took us a few years to be able to see through the mathematics in order to be able to derive equations for the phases. But the consequence of making the mathematical study was to give rise to a variety of relationships among phases and the phases and the intensities so that we would have formulas for carrying out structure determinations. These are the two most used formulas among the phases in order to carry out a structure determination. Some of you might have some interesting questions in your mind. If you define a phase in terms of other phases and you don't know the values of the phases, how do you ever get started to carry out a formula like this in order to get answers? I just might mention that the meaning of this is that this is a phase associated with a plane given by this vector H which actually has three components in the vector. And you need the three components to describe the three dimensional plane. This is a different plane and this is still another plane. And you see if you add this number, this vector, to these two vectors that you end up with that vector. And these phases contained in this formula, this symbol indicates that these are all associated with planes that have the highest intensities. Will we get back to the question, how do you use a formula like this if you have no phase information? And the answer is you do have phase information. You're allowed to specify a certain number of values for the phases and that corresponds to specifying an origin point in the crystal, a point from which all other atoms can be, all atoms can be located. It's like an origin in a coordinate system. And then one way to do is to assign values for a few more phases by the use of symbols. And it turns out that this problem is so over determined that you need very few initial phases in order to be able to proceed with formulas such as this. For example, when you have a center of symmetry, you have phase values that are only zero and 180 degrees. And it's possible to go through phase determinations with probabilities that are as high as 0.99 and greater. And so you just need a small set and you can get started with very high probabilities. And as more and more phases are added in a stepwise fashion, it cascades and you get very large numbers of phases. And you can then use these phase values together with their associated magnitudes, intensity values, and calculate the Fourier series and computer structure. This is an implication concerning the cascading of phase information that some initial specifications, alpha, beta, and gamma, lead to new phase information. And this continues along, the implication of this part of the diagram is that from two different paths you get information about the same phase. And when that starts to happen, you get indications of internal consistency and the fact that the phase determination is on the right track. Now I'd like to talk about some applications. You may recall that Cedric was talking yesterday about the very interesting photo rearrangement reactions that take place in organic chemistry. And I myself find photo rearrangement reactions very appealing because you get major changes major unanticipated changes in the structures. And they're good problems for structure determination because that's a good way to find out about the major changes that often take place in a molecule. This is what's called the pharmacodynamic amine, which means that it's active physiologically. And the people who began to study this and used some ultraviolet radiation were just hoping that they had a nice way to make ring closures in which this carbon atom would attach itself to some place like this and just make a nice closed ring system. Well, one of the major constituents that are major products that they ended up with was something with a formula such as this. Elemental formula, carbon, 12 carbons, 15 hydrogens, 1 nitrogen, 3 oxygens with a melting point of 123 degrees. A structure analysis indicated that the photons and the molecule had minds of their own. And what actually happened was to generate a fused ring system of this kind, something quite different than what appears here, in which one obtains two five-membered rings and two four-membered rings and this arrangement. After you obtain a result like this, it's possible to conceive of a mechanism, a path that may have taken place in the reaction. And as seen here, if this nitrogen attaches here and this carbon attaches here and some hydrochloric acid is lost, you can account for this fused ring system of two five-membered rings and two four-membered rings. This slide illustrates in somewhat more detail how the result comes up in X-ray diffraction analysis. Actually what you get is just a series of peaks such as this plotted at A-axis that refers to the X, C-axis, the Z. And these numbers associated with the points tell you how far along the B-axis perpendicular to these two-dimensional coordinates one finds the peak. Then the question is how do you connect up these points? Well you make a calculation of interatomic distances for the points and since interatomic distances are quite constant in structures, you can easily determine which atoms need to be connected to which. And this is a drawing of how the actual result appeared, the five-membered ring, five-membered ring and the two four-membered rings that were written out in a two-dimensional fashion on the previous slide. Here we have another kind of a study, adduct formation. This problem came up in an interesting way as a gentleman who is trying to find out if there is anything that ascorbic acid does in helping with cancer therapy. And this molecule of acrolein ascorbic acid and it turns out that a crystal structure analysis showed that this fused ring system had occurred between the two so that there is a reaction between the acrolein and the ascorbic acid and it forms a material such as this. Again the way to find out what this looked like readily was by crystal structure analysis. After you know this it's possible again to think about a possible mechanism which is indicated here. This is a rather interesting result we are told by the person who gave us this material that not only is this acrolein which is a rather toxic material in the system and comes from certain therapies. Not only is that in a sense its effect neutralized by attaching to the ascorbic acid but in addition to that this fused ring system has cytostatic effects which means that it stops cells from dividing. An additional application of structure determination is one in which in many circumstances one obtains very small amounts of material from particular reactions or extractions of natural products. A very small amount of natural product which has very potent behavioral characteristics that has been of interest to our department of agriculture. This material is called breast inline and it was observed by people in the department of agriculture that it's very likely that there is a growth hormone, a growth stimulator in the pollen of various flowers. And it was decided to try to obtain this potent growth stimulator. The way this was done was to fool bees in a beehive. Brushes were put right in front of the opening of many, many hives and literally hundreds of pounds of pollen were brushed off the legs of bees and collected for the extraction purpose. From this a very small quantity of material, active material was obtained that was grown into crystals. And the chemists who did not have much material to work with correctly determined that there was probably a steroid involved. This is just the crystal structure result of this triply fused system. This material was breast inline, the growth hormone, and what was very difficult for them to imagine and determine was the fact that the B ring in the steroid was really in this case a seven-membered ring with this extra oxygen here. And it was possible from the structure analysis, of course, to determine this. And it seems from all indications that this extra oxygen, the seven-membered ring formed out of B, is particularly associated with its abilities to enhance growth. Now, I might point out that its effects take place in nanogram quantities. And it is a general growth stimulator. Now, what the chemist wants to do when he finds out what it is that he would like to synthesize is then proceed to do this and do it on the large scale. Well, it turned out that it's quite difficult, at least up to this point, to synthesize this particular compound that has been done. But it's very easy to synthesize other compounds with some minor differences up here in this side chain. And they're also just as active. And so now this material or its close relatives is available in large quantity and is undergoing tests, field tests for the growth of a variety of materials. In nanogram quantities, it will easily double the size of the plant in the same time span. So it's a very effective material. This is an illustration of how you can get precise bond lengths. And the next slide will show bond angles. As a gentleman, Professor Gustav and his student at the Rockefeller University was hoping to make a compound that looked pretty much like a window pane. And that's where the fenestrain comes from. Actually so far all that could be done was to make this five-membered ring instead of a four-membered ring in this particular place. But what this illustrates here is that you can also get fairly precise information about interatomic distances and molecules, and the point about the homofenestrain is that the interatomic distances vary considerably more from carbon-carbon distances than one finds normally in organic compounds. Normally numbers like 1.54 to 1.56 are what are to be expected. But here we see with this strained structure numbers that go up as high as 1.60 and as low as 1.49. The bond angles are also pretty strange. Normally, again with carbon compounds, you find something near the tetrahedral angle which is around 110 degrees with some greater variation than in the case of bond angles, but nothing as great as normally as 86 degrees and 124 degrees and so forth. So there's really quite a lot of strain in this molecule and it's readily detected. The last application that I would like to show is a study of conformation. This is the molecule of Unkephalin. Its structure was solved as many of these others by Mrs. Carl. It occurred in the unit cell with four different conformers. You might notice here that the backbone illustrated by the open atoms is pretty much the same in all four conformers. But the side groups, made out in black, are considerably different on each one of these. There's always the question, do the conformations that occur in crystal structure analysis have anything to do with physiological activity and solution? And the answer is that one must always be cautious. However, in those cases when you get crystallization with large amounts of solvent, then they can be some confidence that there is a reasonable relationship between the crystal structure and the solution. This is particularly agreeable so far as macromolecules are concerned because as you know, for example, proteins always crystallize with very large amounts, 40, 50, 60 percent of solvent water. People here with this Unkephalin, some of you may know that it's a natural analgesic, a natural painkiller. Some people allege that its concentration goes up in the blood supply and the stress, and they think that it accounts to the fact that some people run too far and too much per week at any rate they think they get Unkephalin highs as they're called. And here we see that structure determination of this rather complicated structure that had over 200 atoms in the asymmetric unit could be carried out. This is how they appear in the packing in the unit cell. This arrangement actually is called the beta sheet, and it's formed from the attachment of the various conformers through hydrogen bonding. This, these long lines here are indications of hydrogen bondings to form this beta sheet. I think that's my last line. This sort of summarizes the scientific part of my talk, that the kind of information that you can obtain is chemical identification, structural formula, stereo configuration. If you do special things, you can get absolute configuration, conformation, bond lengths and angles, and if you do some very careful experiments, you can even get charged distributions. I've come to the end of my talk, and I hope that at least one part of it has given you some useful information. Thank you very much. Thank you.
 Good morning.  That's all the German you'll get from me.  Sorry.  It's very pleasant to be here in Lindau.  This is my first visit.  I hope it's not my last.  My talk this morning is divided roughly into three parts.  The first part might be considered advice to young people.  I do so with great hesitation.  I'm not used to handing out advice, and I'm somewhat apprehensive about doing so.  The second part of the talk will, in some sense, be an indication of how the remarks  that I initially make apply to my own life experience.  And then, since I can't resist talking about science and my own field, there will be some  discussion about some applications of crystallographic techniques to chemistry.  I would like to start off by illustrating my apprehension concerning advice by telling  you a little story.  It was a little girl, I suppose, about eight years old, about the third grade, and she had  a homework assignment.  The members of the class were asked to write a small composition about a famous person  in history, and she decided to write about Socrates.  She wrote a little composition that went something like this.  Socrates was a Greek.  He gave people advice.  They killed him, and with that apprehension I'll continue.  At some time in a person's life, it is worthwhile, if not necessary, to make decisions concerning  the path to be followed, that is, the profession that would be most attractive and how it is  to be pursued.  The earlier that such decisions can be made, the better.  Although enough interest and determination, with enough interest and determination, such  decisions can often be delayed until adulthood.  It is not so important to make a detailed decision.  What is important is to decide upon the direction of one's interests so that appropriate education  and training can be pursued.  I had the good fortune of knowing at an early age that I wanted to be a scientist.  I really did not know what kind of a scientist I wanted to be, and it did not seem to be  important to make such a decision.  By the time I was about nine years old, I was already reading about scientific and technical  subjects, and I found that such reading was more interesting than the usual literature  devoted to young people.  There was little question in my mind that science would occupy my future, and I was  committed and determined to make sure that that was the case.  It is apparent that a deep interest in a subject or area of activity, and a personal identification  and respect for a subject or activity, is a very strong motivation that can carry a person  beyond the potential adversities that so often appear to inhibit the achievement of a person's  goals.  In my case, I obtained an advanced degree in science after many adversities, and artificial  barriers were overcome.  The barriers were of various types, economic and social, which had nothing to do with the  science that held my interest or my competence to pursue it.  They nevertheless could have been quite demoralizing, and may very well have discouraged other people  under similar circumstances.  The economic difficulties took the form of not being able to afford advanced education,  and the social barriers concerned quotas and limitations on the support of advanced education.  A strong motivation and dedication to the future can overcome impediments and lead to  a successful career.  It is important to recognize that in order to accomplish almost anything worthwhile,  hard work and dedication are required.  But if a person is content with his or her choices in life, even if the hard work is  not always a joy, it can be satisfying.  Satisfaction derives from progress and an occasional accomplishment.  Hard work, especially intellectual hard work, for protracted periods is achieved only with  motivation, the motivation that derives from commitment to a specific course in life.  Numerous examples can be derived from the world of basic science.  For example, a deep interest in basic science can motivate people to investigate problems  simply for their scientific interest, and not primarily for the recognition that may  come from colleagues for solving problems, for the immediate usefulness of solutions,  or for potential monetary gain.  Purely and simply, it is possible to have such an interest in one's chosen activity  that other attractions and pressures are not able to distract a person from his or her  true interest in life.  Basic science very often ultimately leads to very useful results, but utility as a goal  without the aspects of scientific challenge and an appeal to scientific curiosity would  not generally be an attractive activity for someone with a strong interest in the pursuit  of basic science.  Just as there are often barriers to the achievement of an adequate education in the normal course  of events, life and nature provide numerous barriers to the achievement of one's goals.  To become discouraged instead of staying with one's goals will result, evidently, in  the failure to realize one's potential.  Again, motivation can play a major role in overcoming adversities.  Along with dedication and hard work, it is often necessary to have persistence, sometimes  great persistence.  My own experience showed this to be true.  It was about ten years of hard work and persistence before a general procedure was developed for  making practical applications of the foundation mathematics for crystal structure determination  for whose development the latest Nobel Prizes in chemistry were awarded.  Under development of the foundation mathematics, there were many difficult steps that required  testing and discovery.  These steps are called by some bridging.  In a simple way, I regard bridging as the modification of mathematics so as to be suitable  for application to experimental data and modification of the experimental data so that it could be  suitable for use with the mathematics.  In complicated problems such as the determination of the three-dimensional atomic arrangements  in complex structures, bridging can be a rather difficult and tedious area of intellectual  activity.  This was certainly the case, and it largely accounted for the considerable time between  the development of foundation mathematics and the development of general procedures  for widespread application of the theory.  Structures in the range of about 100 to 400 atoms often present problems that are difficult  to overcome.  There are therefore still some hard problems remaining in structure determination.  In addition, there are indications that improvements can be made in the way the techniques for  macromolecular research are carried out.  Macromolecules can be described as structures having about 500 or more atoms whose positions  need to be determined.  Several techniques can be applied to macromolecules that make them easier to solve than some structures  having fewer atoms.  The motivations that played an important role in bringing structure research to its present  state of high competence and reliability also motivate the pursuit of current fourth  end problems.  I have been implying that it can be very satisfying to be strongly motivated and to set high goals  in life.  Such an approach may necessarily lead to an easy course through life and may not provide  what one personally regards as success.  It is important to be satisfied with trying one's best.  There are many documented circumstances in which young people set very high goals which  they may not ever achieve or at least as soon as they would hope or expect.  With the consequence that a lack of self-confidence or great disappointment and this despondency  may accrue, such mental states can be dangerous and damaging.  It is important to learn how to live with adversity.  As life proceeds, almost everyone has to make compromises with the circumstances in which  they find themselves.  It is easier to accept circumstances that may not be ideal when a person's primary interest  in life, the one for which a person has strong motivations, can be pursued.  If you are convinced that your goals are worthwhile, stay with them and try not to make destructive  compromises.  If your primary objectives are matters such as wealth, power, recognition, easy living,  a scientific career is probably not a particularly good way to achieve such goals.  Such motivations would appear to run counter to a creative scientific career.  Naturally, someone may decide from an early age that his or her goal in life is to be  wealthy.  Many of the personal characteristics that I have described for successful pursuit would  still be applicable.  Beyond that, I personally have no recommendations for such a career.  It is also important to understand that in the course of a person's life, especially  in the sciences, it is very rare that high recognition will be achieved.  And setting recognition as a primary goal can only serve to interfere with the pursuit  of science for its own sake.  In my view, the greatest satisfactions come from the act of scientific discovery, and  it is a valuable asset to be able to derive great satisfaction from personal participation  and discovery, whether or not one's colleagues recognize the value of the work.  A large part of success in life comes from having clear goals and the proper outlook.  If the proper outlook includes personal satisfaction from personal achievement, it is possible  to look forward to a life of joy and a life of accomplishment.  That's all the advice I have.  I would like to continue with the talk now by discussing my own field of research in  the context of motivations that I've had, and also to illustrate, if I may, how one  and sort of broad outline, broad brush outline, how one can go from the measurement of the  intensities of X-ray scattering to a complete molecular structure.  The subject is the three-dimensional structure, atomic arrangements of molecules, as obtained  from so-called X-ray diffraction applied to the crystalline state.  Through the advent of modern technology such as computers, electronics, instrumentation,  and sophisticated computer programming, it has become possible to mount a small single  crystal of an unknown substance on an automatic X-ray diffractometer, and with minimal human  intervention see the complete geometric arrangement of atoms in the molecule displayed on a video  screen.  Depending upon the size of the molecule, the process may take as short a time as one day.  Automatic structure determination is feasible today for very many small and medium-sized  structures, particularly if the crystal contains a center of symmetry.  Larger and more complex structures require the special expertise of professional crystallographers.  The present ease of structure determination, and even the possibility of deriving a structure  from X-ray data, stems from the fundamental theoretical and practical advances made in  solving the phase problem.  What happens is that a collimated beam of X-rays of a particular wavelength is made to impinge  on a single crystal, and that crystal is rotated about various axes, different sets of scattering  planes.  Acting like a ruled grating, come into position for the X-ray beam to be diffracted.  The intensity and the angular orientation of hundreds or thousands of reflections are  measured and recorded by an automatic diffractometer, formerly by photographing.  The phases associated with the diffracted beam, however, with rare exception, cannot  be measured experimentally, and you need the phases as well as the intensities.  Let me see if I can get my first slide.  This is called a Weisenberg photograph.  Each one of the spots comes from a particular plane in the crystal, and its location can  determine by a fairly simple geometric calculation what particular plane in the crystal scattered  each of the spots.  And as you notice, they have varying intensities, some are very light and very difficult to  see, others are so black that it's difficult to estimate their intensity.  Many years ago, perhaps over 20 by now, this was a general technique for obtaining X-ray  diffraction information, and it was necessary to sit for sometimes several months with a  comparison strip and make a comparison and estimation of the intensity in each one of  these spots.  Nowadays, all of this is taken care of for you in automatic instrumentation.  I am not going to make a deep mathematical conversation about this business, but this  mathematics here, this function, rho, represents the structure of a crystal because it represents  the density, electron density, in a crystal.  In order to compute this function over here, which is called the Fourier series, you have  to know all about these numbers here.  These numbers are complex numbers, and that means that there's a magnitude and some kind  of an angle associated with them.  And here's where the problem resides.  Those black spots give you information about this part of the number, and superficially,  it appears that they give you no information at all about this angle, which can be called  the phase angle, and you need both this magnitude and this angle in order to compute this function.  The reason why the electron density in the crystal represents its structure is because  atoms are located where electron densities have their greatest value near the peaks of  the electron density function.  So that if somehow or other you could find this, then it's a trivial calculation in a  computing machine to obtain this density function that you wish to have.  Well it was decided that since you only get this part and not that part, that there was  no chance of directly taking x-ray intensity information in order to make this calculation.  And it was actually quite obvious to Herbert Houtman and I that the phase information was  actually contained in the intensity information that was measured and seen in the x-ray diffraction  photographs.  Now it's one thing to know that the answer is there and quite another matter to find  the answer.  And so it took us a few years to be able to see through the mathematics in order to be  able to derive equations for the phases.  But the consequence of making the mathematical study was to give rise to a variety of relationships  among phases and the phases and the intensities so that we would have formulas for carrying  out structure determinations.  These are the two most used formulas among the phases in order to carry out a structure  determination.  Some of you might have some interesting questions in your mind.  If you define a phase in terms of other phases and you don't know the values of the phases,  how do you ever get started to carry out a formula like this in order to get answers?  I just might mention that the meaning of this is that this is a phase associated with a  plane given by this vector H which actually has three components in the vector.  And you need the three components to describe the three dimensional plane.  This is a different plane and this is still another plane.  And you see if you add this number, this vector, to these two vectors that you end up with  that vector.  And these phases contained in this formula, this symbol indicates that these are all associated  with planes that have the highest intensities.  Will we get back to the question, how do you use a formula like this if you have no phase  information?  And the answer is you do have phase information.  You're allowed to specify a certain number of values for the phases and that corresponds  to specifying an origin point in the crystal, a point from which all other atoms can be,  all atoms can be located.  It's like an origin in a coordinate system.  And then one way to do is to assign values for a few more phases by the use of symbols.  And it turns out that this problem is so over determined that you need very few initial phases  in order to be able to proceed with formulas such as this.  For example, when you have a center of symmetry, you have phase values that are only zero and  180 degrees.  And it's possible to go through phase determinations with probabilities that are as high as 0.99  and greater.  And so you just need a small set and you can get started with very high probabilities.  And as more and more phases are added in a stepwise fashion, it cascades and you get  very large numbers of phases.  And you can then use these phase values together with their associated magnitudes, intensity  values, and calculate the Fourier series and computer structure.  This is an implication concerning the cascading of phase information that some initial specifications,  alpha, beta, and gamma, lead to new phase information.  And this continues along, the implication of this part of the diagram is that from two  different paths you get information about the same phase.  And when that starts to happen, you get indications of internal consistency and the fact that  the phase determination is on the right track.  Now I'd like to talk about some applications.  You may recall that Cedric was talking yesterday about the very interesting photo rearrangement  reactions that take place in organic chemistry.  And I myself find photo rearrangement reactions very appealing because you get major changes  major unanticipated changes in the structures.  And they're good problems for structure determination because that's a good way to find out about  the major changes that often take place in a molecule.  This is what's called the pharmacodynamic amine, which means that it's active physiologically.  And the people who began to study this and used some ultraviolet radiation were just  hoping that they had a nice way to make ring closures in which this carbon atom would attach  itself to some place like this and just make a nice closed ring system.  Well, one of the major constituents that are major products that they ended up with was  something with a formula such as this.  Elemental formula, carbon, 12 carbons, 15 hydrogens, 1 nitrogen, 3 oxygens with a melting  point of 123 degrees.  A structure analysis indicated that the photons and the molecule had minds of their own.  And what actually happened was to generate a fused ring system of this kind, something  quite different than what appears here, in which one obtains two five-membered rings  and two four-membered rings and this arrangement.  After you obtain a result like this, it's possible to conceive of a mechanism, a path  that may have taken place in the reaction.  And as seen here, if this nitrogen attaches here and this carbon attaches here and some  hydrochloric acid is lost, you can account for this fused ring system of two five-membered  rings and two four-membered rings.  This slide illustrates in somewhat more detail how the result comes up in X-ray diffraction  analysis.  Actually what you get is just a series of peaks such as this plotted at A-axis that  refers to the X, C-axis, the Z.  And these numbers associated with the points tell you how far along the B-axis perpendicular  to these two-dimensional coordinates one finds the peak.  Then the question is how do you connect up these points?  Well you make a calculation of interatomic distances for the points and since interatomic  distances are quite constant in structures, you can easily determine which atoms need  to be connected to which.  And this is a drawing of how the actual result appeared, the five-membered ring, five-membered  ring and the two four-membered rings that were written out in a two-dimensional fashion  on the previous slide.  Here we have another kind of a study, adduct formation.  This problem came up in an interesting way as a gentleman who is trying to find out if  there is anything that ascorbic acid does in helping with cancer therapy.  And this molecule of acrolein ascorbic acid and it turns out that a crystal structure  analysis showed that this fused ring system had occurred between the two so that there  is a reaction between the acrolein and the ascorbic acid and it forms a material such  as this.  Again the way to find out what this looked like readily was by crystal structure analysis.  After you know this it's possible again to think about a possible mechanism which is  indicated here.  This is a rather interesting result we are told by the person who gave us this material  that not only is this acrolein which is a rather toxic material in the system and comes  from certain therapies.  Not only is that in a sense its effect neutralized by attaching to the ascorbic acid but in  addition to that this fused ring system has cytostatic effects which means that it stops  cells from dividing.  An additional application of structure determination is one in which in many circumstances one  obtains very small amounts of material from particular reactions or extractions of natural  products.  A very small amount of natural product which has very potent behavioral characteristics  that has been of interest to our department of agriculture.  This material is called breast inline and it was observed by people in the department  of agriculture that it's very likely that there is a growth hormone, a growth stimulator  in the pollen of various flowers.  And it was decided to try to obtain this potent growth stimulator.  The way this was done was to fool bees in a beehive.  Brushes were put right in front of the opening of many, many hives and literally hundreds  of pounds of pollen were brushed off the legs of bees and collected for the extraction purpose.  From this a very small quantity of material, active material was obtained that was grown  into crystals.  And the chemists who did not have much material to work with correctly determined that there  was probably a steroid involved.  This is just the crystal structure result of this triply fused system.  This material was breast inline, the growth hormone, and what was very difficult for them  to imagine and determine was the fact that the B ring in the steroid was really in this  case a seven-membered ring with this extra oxygen here.  And it was possible from the structure analysis, of course, to determine this.  And it seems from all indications that this extra oxygen, the seven-membered ring formed  out of B, is particularly associated with its abilities to enhance growth.  Now, I might point out that its effects take place in nanogram quantities.  And it is a general growth stimulator.  Now, what the chemist wants to do when he finds out what it is that he would like to  synthesize is then proceed to do this and do it on the large scale.  Well, it turned out that it's quite difficult, at least up to this point, to synthesize this  particular compound that has been done.  But it's very easy to synthesize other compounds with some minor differences up here in this  side chain.  And they're also just as active.  And so now this material or its close relatives is available in large quantity and is undergoing  tests, field tests for the growth of a variety of materials.  In nanogram quantities, it will easily double the size of the plant in the same time span.  So it's a very effective material.  This is an illustration of how you can get precise bond lengths.  And the next slide will show bond angles.  As a gentleman, Professor Gustav and his student at the Rockefeller University was  hoping to make a compound that looked pretty much like a window pane.  And that's where the fenestrain comes from.  Actually so far all that could be done was to make this five-membered ring instead of  a four-membered ring in this particular place.  But what this illustrates here is that you can also get fairly precise information about  interatomic distances and molecules, and the point about the homofenestrain is that the  interatomic distances vary considerably more from carbon-carbon distances than one finds  normally in organic compounds.  Normally numbers like 1.54 to 1.56 are what are to be expected.  But here we see with this strained structure numbers that go up as high as 1.60 and as  low as 1.49.  The bond angles are also pretty strange.  Normally, again with carbon compounds, you find something near the tetrahedral angle  which is around 110 degrees with some greater variation than in the case of bond angles,  but nothing as great as normally as 86 degrees and 124 degrees and so forth.  So there's really quite a lot of strain in this molecule and it's readily detected.  The last application that I would like to show is a study of conformation.  This is the molecule of Unkephalin.  Its structure was solved as many of these others by Mrs. Carl.  It occurred in the unit cell with four different conformers.  You might notice here that the backbone illustrated by the open atoms is pretty much the same  in all four conformers.  But the side groups, made out in black, are considerably different on each one of these.  There's always the question, do the conformations that occur in crystal structure analysis have  anything to do with physiological activity and solution?  And the answer is that one must always be cautious.  However, in those cases when you get crystallization with large amounts of solvent, then they  can be some confidence that there is a reasonable relationship between the crystal structure  and the solution.  This is particularly agreeable so far as macromolecules are concerned because as you know, for example,  proteins always crystallize with very large amounts, 40, 50, 60 percent of solvent water.  People here with this Unkephalin, some of you may know that it's a natural analgesic,  a natural painkiller.  Some people allege that its concentration goes up in the blood supply and the stress,  and they think that it accounts to the fact that some people run too far and too much per  week at any rate they think they get Unkephalin highs as they're called.  And here we see that structure determination of this rather complicated structure that  had over 200 atoms in the asymmetric unit could be carried out.  This is how they appear in the packing in the unit cell.  This arrangement actually is called the beta sheet, and it's formed from the attachment  of the various conformers through hydrogen bonding.  This, these long lines here are indications of hydrogen bondings to form this beta sheet.  I think that's my last line.  This sort of summarizes the scientific part of my talk, that the kind of information that  you can obtain is chemical identification, structural formula, stereo configuration.  If you do special things, you can get absolute configuration, conformation, bond lengths  and angles, and if you do some very careful experiments, you can even get charged distributions.  I've come to the end of my talk, and I hope that at least one part of it has given you  some useful information.  Thank you very much.  Thank you.
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