Science in Christian Perspective

Chemistry
WALTER R. HEARN

The heading of this column has always been a bit embarrassing to its author because it has often been misleading. Generally, the heading Chemistry has been too broad for the material discussed, which because of limitations of the author has dealt only with one aspect of chemistry, the application of chemical techniques and modes of thought to biological problems. Occasionally the author has tried to justify this narrow emphasis by implying that this is probably the area in which chemistry as a science might have its greatest current impact on theological thinking. At other times the author has been carried away by the grandiose thought that he and other chemists are SCIENTISTS after all, and should be capable of discussing the broader implications of science and Christian faith, no matter how little we have read of the history and philosophy of science, or of theology. In those cases the heading of this column has not been broad enough to describe its contents accurately. Perhaps with the editorial reorganization now taking place this column will no longer appear in the journal, or if so it may be under a more honestly descriptive heading, such as "Idle Thoughts of a Christian Biochemist."

For this particular column, written possibly as a swan song, it may be appropriate to include both kinds of idle thoughts, some biochemical and some philosophical, the author's reflections after attending the 1962 meetings of the Federation of American Societies for Experimental Biology in Atlantic City.

Scientific Afterthoughts

The rate at which biochemical and biophysical investigations are progressing seems almost fantastic, and produces in a biochemist of my generation mixed feelings of excitement and frustration. The excitement comes from a sense of participation, no matter how vicarious, in solving some of the mysteries of life that have always seemed hopelessly inscrutable; the frustration from trying to acquire enough fundamental knowledge to keep up with the latest developments and to gain an adequate comprehension of at least the most important ones. I have forgotten how far back in recent history the "electronic age" occurred, but I think it immediately preceded the "atomic age," which gave way more recently to the "space age" we now seem to be in. The inevitable impact on biochemistry of support by NASA of projects in space biology is yet to be felt. Comparison of an up-to-date "metabolic map" (they are never really up-to-date; I should have said "the latest edition") with one of ten years ago makes one conscious of the debt we owe to the AEC for making isotopic tracers more or less common reagents for elucidating biochemical pathways. Perhaps various agencies of DOD (Department of' Defense) played the major role in sponsoring development of electronics technology, first in the area of radar and other forms of detection and communication and more recently in the area of high-speed computing. At any rate, the impact of this electronic legacy is still being felt in biochemical investigation, particularly in the acceleration of solutions of problems whose complexity made them seem completely beyond our grasp only a few years ago. The automation boom is on in research already.

A dramatic example of acceleration due to the availability of high speed computing machines is the fact that the complete three-dimensional structure of a globular protein, myoglobin, has now been worked out from the data of X-ray diffraction alone, and most of the structural details of a much larger protein, hemoglobin, have also been obtained by the same method. I believe I heard Linus Pauling say once in a lecture that he started doing X-ray studies of amino acids and simple peptides with the hope that in twenty-five years he would be able to use the data obtained in interpreting the complicated diffraction patterns of large protein molecules, but the availability of electronic computers enabled him to do it in only fifteen years instead. At any rate, the alpha-helix, most widely known configuration of polypeptide chains, was first proposed by Pauling, Corey, and Branson in 1951. For myoglobin, of molecular weight 17,000 and containing 150 amino acid residues in a single polypeptide chain, J. C. Kendrew and his co-workers at Cambridge published the first three-dimensional electron-density map in 1958 and a more detailed account in 1959. The first map at 6-A resolution was based on phase determinations for the 400 reflections closest to the center of the diffraction pattern; taking the resolution to 2-A involved measurement of 10,000 reflections for the protein itself and for each of four derivatives, with computing programs for Fourier synthesis being worked out for one of the large electronic computers, the Cambridge EDSAC II. For hemoglobin, a molecule four times the size of myoglobin and containing four heme prosthetic groups instead of one, and two pairs of different polypeptide chains instead of a single chain, M. F. Perutz has published a map in 1960 with detail comparable to that of Kendrew's 6-A map of myoglobin. For an excellent review with photographs of some of the, projections and molecular models constructed from them as well as references to the original papers, see A. Rich and D. W. Green, "X-ray Studies of Compounds of Biological Interest," Annual Review of Biochemistry, 30, 93-132 (1961). For an exciting senii-technical account of the myoglobin solution, see J. C. Kendrew's "The ThreeDimensional Structure of a Protein Molecule," in Scientific American for December, 1961.

The huge attendance at the symposium on Genetic Mechanisms at the 1962 Federation shows the great interest in this area of biochemistry at the present time. Particular emphasis was given to what has become known as "the decoding problem," a field in which the investigators themselves seem rather astounded that the work is going so fast. The "code" referred to is of course the sequence of nucleotides making up DNA or RNA-the giant nucleic acid molecules containing genetic information in linear array, just as these lines of type contain information accessible to you at this moment because they are linear non-random arrays of letters of the English alphabet. The information conveyed by a particular triplet of the four possible nucleotides is that which specifies the positioning of a single amino acid (one of twenty "letters" in the protein alphabet) in a protein as it is laid down on an RNA template in the ribosomes, the protein manufacturing particles of cells. In cells, the DNA of the chromosomes in the nucleus is essentially the master blueprint; this is copied on "messenger" RNA, which carries the information to the ribosomal or "template" RNA, perhaps by becoming part of the template itself. A few years ago a specific "transfer" or "soluble" RNA for each amino acid was found to be an essential part of the process of protein synthesis, since amino acids had to be bound to this transfer-RNA in order to be transported into the ribosome and lined up on the template. From the beginning it seemed obvious that each of these specific transfer-RNA's must contain somewhere in its structure the nucleotide code (or its complement, an inverse kind of code) for one amino acid of the twenty. Although the size of these smallest types of RNA was still considerable for doing nucleotide sequence studies (possibly a hundred nucleotides), it was still considered that exploration of their structures offered the best hope of ever "breaking the code."

However, two other independent pieces of research provided the keys with which the code is actually being broken at present, completely by-passing studies of transfer-RNA. One of these was the use of both cell free polynucleotide-synthesizing enzyme systems and protein-synthesizing enzyme systems of bacteria; it was found that when a single nucleotide precursor such as uridine triphosphate (UTP) was supplied to the former system, the product would be an artificial polynucleotide containing a single nucleotide, in this case poly-U. Severo Ochoa of New York University did the pioneering work on polyribonucleotide synthesis and in fact recently won the Nobel prize for it, but M. Nirenberg of the National Institutes of Health then used these polynucleotides as templates in the second kind of enzyme system and discovered that a homo-polynucleotide, poly-U, led to synthesis of a homo-polypeptide, poly-phenylalanine (poly-Phe). In other words, the triplet of nucleotides which specifies Phe in a protein must be UUU, and we have begun to decipher the code!

The second type of research providing keys to the coding problem has been work with tobacco mosaic virus (TMV) carried on primarily at two special institutes for virus research, one at the University of California in Berkeley and the other in Tiibingen, Germany. Chemical relationships between the nucleotides in RNA are such that one nucleotide can be converted to one of the others by mild chemical treatment: specifically, nitrous acid converts an amino group to a hydroxyl group, making cytidine (C) into uridine. Although the work is very laborious and time-consuming, even with automated analytical equipment, the principle is essentially simple: RNA from normal TMV is treated gently with nitrous acid, converting some of the C into U and producing a chemically manufactured mutant. The mutant virus is cultivated until enough is available to p,-rmit isolation of the now abnormal protein coat around the RNA core of the virus, and this protein is broken down into fragments which are analyzed y careful quantitative methods to see what "damage" the mutation of RNA caused in the protein; many of the abnormal proteins have shown specific substitution of one amino acid for another, and in general (with some exceptions) these substitutions have been in accord with the data from the other type of decoding research. For example, if UUU really codes for Phe, then treatment with nitrous acid should never lead to substitution of Phe by some other amino acid, since C is always changed to U in the RNA and never U to C. On the other hand, if Phe is found to substitute for another amino acid in some position in the peptide chain, then the RNA code for that amino acid is likely to be UUC, UCU, or CUU, and so on. Careful analysis has already led to development of a nucleic acid code for about half of the amino acids. A good semi-technical discussion of the background for this research can be found in two articles on "The Chemistry of Life" in Vol. 39 of Chemical and Engineering News: "How Cells Synthesize Proteins" (pp. 80-89, May 8) and "Implications of Recent Studies of a Single Virus" (pp. 136-144), May 15, 1961). A reprint of these two articles bound together with a third, "How Life Originated on Earth and in the World Beyond" (pp. 96-104, May 22, 1961), is available for $1.00 from C&EN.

One problem which has often occurred to me in thinking about the mechanism of genetic mutation is that of back-mutations, and one paper presented at the 1962 Federation meetings by C. Yanofsky of Stanford University contained a most beautiful example of a mechanism for this phenomenon. A series of mutants of a micro-organism which lacked an active tryptophan synthetase enzyme were studied, and in one case a mutant arising from one of these mutants was obtained which could grow on a tryptophanless medium, indicating that the enzyme was again active. It was found possible to isolate the active enzyme from both the wildtype and the back-mutant organisms, and a very similar but inactive protein from the tryptophan-requiring mutant giving rise to the back-mutant. By die remarkable technique of "fingerprinting" to locate possible amino acid substitutions (the same procedure used in the TMV protein studies described above), Yanofsky was able to show that the inactive protein was identical to the wild-type enzyme except for a single substitution, and that the back-mutation had resulted in a second substitution at a different location in the peptide chain, this time restoring enzyme activity to the inactive protein, no doubt by permitting a refolding of the secondary protein structure to make up for the "kink" put in the chain by the first mutation. In other words, the back-mutation was not a simple reversal of the original mutation, but a further change which happened to result in a protein which also had the same biological activity as the original enzyme.

I left the symposium on Genetic Mechanisms thinking what a poor time this is for opposition to evolutionary ideas on grounds that they "are only theories without empirical evidence or plausible mechanisms to back them up." Well, mutations are certainly getting a lot less mysterious than they used to be--and we have been able to determine structures of biological macromolecules for only a very few years now. The handwriting is on the DNA!

Philosophical Afterthoughts

The Federation joint meeting has become one of the largest scientific meetings in the world, with perhaps 20,000 scientists in attendance and more than 3,000 papers describing new research findings being presented in a single week. Manufacturer's equipment exhibits at the 1962 meeting emphasized expensive and complicated automated equipment for doing more and better research-and doing it much faster. I heard several comments about how many badges indicated the wearer as being from NIH or some other large research institute, sometimes with a note of annoyance, regret, or nostalgia for "the good old days" when biochemistry was done by individuals or small groups in widely scattered university laboratories. Our science seems to be growing and changing so fast that it almost seems to be getting out of hand, and we are beginning to feel it personally. It is easy to see why the brightest people are attracted to large institutes: in biochemistry it is still easy for an individual investigator to have a brilliant idea on his own, but it is difficult to test it out adequately without expensive equipment, technical assistants, and automated analytical facilities. No wonder young scientists who feel themselves capable of original thinking want to go to huge, well-equipped laboratories where their ideas can get rapid and thorough experimental verification, and where they will be "in" on the latest results from related work of the most active investigators. The trend in this direction seems inevitable, and our pleasant little science begins to feel both the blessings and curses of bigness.

In the midst of thoughts about these problems, about individual research people I talked to at the meetings concerning their personal as well as scientific struggles, and about a few opportunities I had to witness directly or indirectly to colleagues concerning my faith in Jesus Christ, I was struck by the passage about our Lord: "He had compassion for them, for they were like sheep without a shepherd." What an opportunity ASA members have to share the Good News of Christ's redemption with their colleagues! Some of my friends who have always looked to science for personal satisfaction are expressing a growing sense of their own "lostness" in a context which only a fellow-scientist could appreciate. Has the Christian church as a whole made any effort to understand these problems and to minister to the special needs of scientists? Has the church tried to understand enough of the nature of moral choices scientists face in their professional lives to give appropriate guidance and counsel? Has the church valued the work of scientists, respected their frame of reference, and tried to communicate the Gospel in their own language, to speak to their particular psychological and intellectual needs?

There seems to be little evidence for a sympathetic understanding of science or of scientists by the church as a whole, and considerable evidence of lingering suspicion or even hostility left over from battles fought in the past between misguided interpreters of science and theology. Attending a local church in Atlantic City right in the very midst of the Federation meeting reinforced this impression and reminded me forcefully that it is only we who are members of both communities who can bridge the gap between them, and we must do it even at the risk of being misunderstood by fellow Christians as well as by fellow scientists. Is it not true that church-centered Christian education began with the Sunday School movement only about a hundred years ago, and That largely out of a need to teach underprivileged children how to read so they could understand the Bible even if they had no other opportunity for schooling? Today I think there is a need to teach enough science to "scientifically underprivileged" Christians to enable them not only to comprehend what goes on around them in a science-oriented culture but especially to help them avoid inadequate or foolish interpretations of Scripture. This is one great challenge for the ASA; the other is to be Christ's men among scientists, for whom He also gave His life. It is true that the Gospel is to be preached to the poor, and this includes the intellectually poor-but must it be preached only the intellectually poor?

Dept. of Biochemistry and Biophysics Iowa State University, Ames, Iowa