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Collecting the Foundations of Molecular Biology—Records of Discovering the Secrets of Life Jeremy M. Norman

Discovery of the double helix and related developments in molecular biology changed our view of life from the microbiologist’s world of the cell to the molecular biologist’s view of the structure and function of individual molecules and their interaction. These discoveries opened a whole new, incredibly intricate, and unspeakably beautiful universe of life forms and functions on the molecular level, and caused the development of new ideas and vocabulary to explain them. They brought advances in quantum physics to the life sciences. The scientists whose work is recorded in this collection knew that they were exploring a new universe in this micro-world, but in the 1950s they could not see the vast consequences of their discoveries, or their wide impact upon society. Rosalind Franklin who died in 1958 did not live long enough to see the consequences at all.

The Solution to an Ancient Riddle-How Genetic Information, and Variation in Species is Preserved

The development of molecular biology has often been called the most significant change in biology since the revolution caused by Darwin’s discovery of evolution by natural selection. Yet those who make this assertion usually give no specific reasons why the assertion is true. In terms of fundamental ideas and concepts, one of the greatest achievements of molecular biology has been to answer a central question that Darwin’s work raised but could not answer—how nature maintains variation in the population of different species. In formulating his theory of natural selection Darwin observed the constant variation in species populations. Rather than conforming to ideal types, species populations exhibit a wide variation in numerous observable traits. Darwin collected large amounts of data concerning variation in species populations, and demonstrated how, through the mechanism of natural selection, variations that happened to become advantageous in a changing environmental situation, as a result of climatic change, new diseases, survival against a new predator, or some other reason, would allow the variant to survive and reproduce more successfully than other members of the species population. As a result of this greater reproductive success, over a series of generations, the advantageous variation would be introduced to most of the species population. Working with variations in the species population, natural selection allows the species to adapt and survive in changing environmental conditions.

What Darwin knew little or nothing about was how variation was maintained through the hereditary process. Concerned with the effects of natural selection on species populations, Darwin thought in terms of entire animals and their behavior—not individual cells. When attempting to understand how traits were passed from generation to generation Darwin expressed in general terms traditional theories of heredity that involved the blending of genetic information over many generations and thousands or hundreds of thousands of years. Like most scientists of his day, Darwin was unaware of Mendel’s discovery of a particulate theory of heredity (1865). Darwin’s traditional ideas about genetics could not explain how variation was consistently maintained in species populations. Blending of genetic information would have had the effect of eliminating variation—the essential raw material for natural selection. If you breed a black mouse with a white mouse and the genetic information blends, theoretically all the offspring would be a blend of black and white, or some shade of gray. More significantly the offprint of this breeding would always remain gray. Nevertheless it was commonly known that this blending does not occur.

Finding how the genes actually operated and how the genetic information was replicated over countless generations was the historic challenge of genetics. After about 1900 when the Mendelian, or particulate theory of heredity was accepted by the scientific establishment, learning how the genetic information was processed became the task of geneticists. How traits were passed from generation to generation, how diseases were inherited, how traits spread through populations were subjects of genetics research. But until 1953 there was no precise explanation of how genetic information was actually passed from generation to generation in such a way that specific data, the cause of individual variation, was maintained. In discovering the double helix and its means of replication that showed how DNA could store and replicate genetic information, James D. Watson and Francis Crick and associated scientists solved an ancient riddle that Darwin and Mendel had attempted to address about 100 years earlier using the very limited information of their time. This riddle was indeed “the secret of life.”

How Nature Constructs Proteins from the Genetic Information

Prior to discovering the double helix, Watson and Crick and their colleagues worked in an environment of X-ray crystallography and molecular biology in which the structure of proteins and the structure and function of nucleic acids were thought to be interrelated, but the means of their interrelationship was unknown. For a long time DNA was thought to be a protein. The double helix was the first key to understanding how nature constructs proteins from genetic information. It was the first of numerous keys required to unlock these most intricate of nature’s secrets.

As we now know, proteins assemble themselves. “The key principle that runs through these systems is the notion of specificity, which enables the different constituent molecules to recognize each other and exclude others that do not belong, so that no external instructions are necessary to form the assembly. In other words, the design of an ordered structure is built into the bonding properties of its constituents, so that the system ‘assembles itself’ without the need for a scaffold.” (Aaron Klug, Leonardo, 1997). Discovery of the much more complex process of the conversion of essentially two-dimensional genetic information stored in the double helix of DNA into the synthesis of three-dimensional protein molecules, many of them containing as many as 10,000 atoms, involved discoveries by numerous scientists, of which Max Perutz was one of the earliest and most influential pioneers.

A. The Structure of Myoglobin and Hemoglobin

When Perutz began his research in 1937 little was understood about the structure and function of proteins. Just as little, or even less, was understood about the molecular structure of the gene. There was, as yet, no convincing evidence that DNA contained the genetic information, and there was no understanding of the mechanism that the cell used to cause proteins to be constructed. Nevertheless it was believed by X-ray crystallographers that the secret of life lay in the structure and function of proteins. Thus when Perutz began his career with the single-minded purpose of understanding the structure and function of the protein, hemoglobin, he did so independently of genetics. “They [proteins] were regarded as the most important molecules of the living cell, but all we knew was that they are made of polypeptide chains, and roughly the amino acid composition of a few of them.” (Perutz, 1997, xviii). Though knowledge of protein structure gradually evolved between 1937 and 1953 it was only after the discovery of the double helix that scientists began to understand the relationship between the structure of proteins and the multi-faceted method that nature uses to convert extremely complex genetic information into the equally complex structure of proteins.

Starting in 1937, working with his teacher, J. D. Bernal, Perutz would apply the techniques of X-ray crystallography, also called X-ray diffraction or X-ray analysis, to the hemoglobin molecule. Bernal’s teacher and later Perutz’s colleague and frequent co-author, Sir Lawrence Bragg, had invented the techniques of X-ray crystallography in 1912-13. However, before the techniques of X-ray analysis could be applied to proteins these substances first had to be crystallized in such a way that they could be successfully X-rayed.

Because hemoglobin was easy to crystallize, and was also one of the most basic of biological molecules, the history of hemoglobin research was immense. In his library Perutz had a copy, included in his archive, of the reference work by Reichert and Brown concerning the Crystallography of Hemoglobins in different animals as evidence for evolution. This large thick quarto published in 1909, with 600 photomicrographs of different hemoglobin crystals, summarized the work of its authors, and most prior work from the 19th century. Yet in spite of all the early research, the quality of the crystals reproduced in the Reichert and Brown book, while adequate for microscopic examination, was insufficiently concentrated for X-ray analysis.

In the early 1930s John H. Northrop, at the Rockefeller Institute for Medical Research in Princeton, crystallized the enzyme pepsin, which digests proteins in the stomach, as well as trypsin and chymotrypsin that digest proteins further in the stomach. Soon thereafter, in 1934 J. D. Bernal and Dorothy Crowfoot (later Hodgkin) applied X-ray analysis to crystalline pepsin, demonstrating that X-ray analysis could be used to solve the structure of the key building blocks of life—protein molecules. About the same time Wendell Stanley was the first to crystallize a virus (TMV).

Perutz began research on the structure of hemoglobin after he obtained some crystals of horse hemoglobin from which he obtained rich X-ray diffraction patterns. Because of the enormous complexity of the molecule it must certainly have appeared early on in his research that he had only a remote chance of success. Nevertheless, except for a brief period during World War II, in which he was interned in Canada as an enemy alien, Perutz persisted with dogged determination for the rest of his life in research on the hemoglobin molecule. By 1946 Perutz published the first of a long series of basic discoveries in molecular biology based upon his hemoglobin research. Through welling experiments he demonstrated the existence of a layer of “bound water” surrounding a protein molecule. This is “an important concept that is now taken for granted.” (Klug, Max Perutz [1924-2000], Science 295, 2382.) In 1947 the Medical Research Council established a Molecular Biology Unit at the Cavendish Laboratory under Perutz’s direction.

After 17 years of work, in 1954,Perutz was able to solve the structure of hemoglobin in two dimensions. This was the year after Francis Crick, then a graduate student at Cambridge working on a doctoral dissertation on the structure of hemoglobin in Perutz’s laboratory, and James Watson, also in Perutz’s molecular biology research unit at the Cavendish Laboratory, discovered the double helix. Crucial elements leading to Watson and Crick’s discovery was data gained through X-ray crystallography researches, especially those of Sven Furberg and Rosalind Franklin, both of whose work is also extensively documented in this collection.

Also in 1954 Perutz discovered the heavy atom method, or isomorphous replacement, that finally enabled sufficient information to be obtained from X-ray analysis for understanding of the three-dimensional structures of biological molecules. Using this method Perutz’s associate, John Kendrew, was able to build a rough molecular model of myoglobin, a much simpler molecule than hemoglobin. By 1959 Kendrew and his team had computed the electron density map of myoglobin at 2.0?, allowing Kendrew to build a 3-dimensional atomic model, the first of any protein. In February 1960 Perutz and his team determined the three-dimensional structure of hemoglobin. “For the first time the world knew what a protein looked like.” (Klug). For Perutz this was a culmination of efforts begun in 1937. Yet the outline of the proteins did not reveal their inner workings. For hemoglobin there was no hint of the mechanism of respiratory transport during which the four subunits of hemoglobin alter their structure when they take up oxygen. In the process of changing structure the molecules also change color, a change, that is, of course, visible to the naked eye. Perutz would solve this problem later. He would also initiate the molecular study of disease. The papers of Max Perutz, recording his lifetime of research and writing, are present in this collection.

In 1962 Perutz would found the MRC Laboratory of Molecular Biology at Cambridge. This was the first research center specifically focused on molecular biology. While the heavy atom technique of X-ray diffraction that Perutz worked out is used by hundreds of thousands of researchers today, and has enabled the elucidation of many thousands of different protein structures, we should not forget Perutz’s central role as an administrator in fostering the careers of other renowned scientists, and other scientific discoveries of the highest value.

B. The Structure of Tobacco Mosaic Virus (TMV)

When Rosalind Franklin, uncomfortable in the research environment at King’s College, moved in 1953 from King’s to Birkbeck College, London, her supervisor at King’s, John T. Randall, demanded that she discontinue research on DNA. The next subject on which she focused was the tobacco mosaic virus, a topic also of interest to Watson and Crick. While less famous than the double helix of DNA, the tobacco mosaic virus has long been one of the central research topics of structural molecular biology:

“Tobacco mosaic virus is one of the simplest viruses known. Whether or not this simplicity of design is responsbielresponsible for its success, its ready availability has made it convenient for biochemical and structural studies, and its simplicity has helped turn it, in one sense, into a paradigm for studies of biological structure and assembly.” (Klug, A. “The tobacco mosaic virus particle; structure and assembly.” Phil. Trans. Ser. B., v.354 [1999] 531)

By the time of her early death in 1958 Franklin and her team, along with Donald Caspar in the United States, had mapped out the general outline of the structure of the rod-shaped tobacco mosaic virus (TMV). They showed that the structure is “a spiral of RNA which carries the genetic information encased in a helical array of protein units arranged rather like corn-on-the cob.” (Aaron Klug, as told to E. Garfield, Current Contents, 1984). This was the first structure of a helical nucleoprotein to be understood. Continuing research on TMV after Franklin’s death, Klug and his team solved the structure to atomic resolution in 1970, and were later able to prove the mechanism of the assembly, the most detailed system of its kind that has been worked out.

With the discoveries of the first protein structures, and a radically new view of the way that nature stores and replicates genetic information, enormous challenges remained in the classical period of molecular biology to show how the information stored in DNA is communicated to the cells to produce proteins. Between Crick’s formulation in 1957 of his “sequence hypothesis” and “central dogma” and 1966 discoveries of messenger RNA (mRNA), transfer RNA (tRNA), and the genetic code led to the basic understanding of how the information in DNA could be transferred to the site of protein manufacture in the cytoplasm. These radical discoveries revolutionized our basic understanding of life processes, stimulating a growing enterprise of research that lead eventually to bioengineering and biotechnology in all advanced countries. Later, as the human genome was mapped (2000) it was discovered that the human genome has about 100,000 coding regions, and that perhaps 100,000 different proteins may be involved in the human genome. The process of solving the protein structures begun by Max Perutz in 1937, and carried forward to the first successes by Perutz and Kendrew in 1954, eventually led, through the efforts of many researchers, to the enormous enterprise of what came to be called “structural genomics”—solving the protein structures as a part of realizing the potential of genome data for advances against disease.

Approaching a Highly Technical Subject from the Collector’s Point of View—The Role of Key Players in the Drama of Discovery

Like an epic drama, the founding discoveries of molecular biology may be viewed as a series of interrelated stories understandable on different levels of human interest and scientific detail. How these epochal discoveries became known to the world outside the laboratory is also a fascinating aspect of the overall history. Here James D. Watson’s celebrated account, The Double Helix (1968) played a central role. Were it not for this classic of popular science the story might not be so widely known.

Within this collection on the foundation of molecular biology are original manuscripts, correspondence and other original documentation of discovering the secrets of life, and the controversy over Watson’s autobiographical account. There is also very extensive documentation of numerous other discoveries of major historical consequence, as well as the record of day-to-day scientific work by significant researchers. Because most of the pioneers in the early days of molecular biology knew and interacted with one another, papers in this collection often record their correspondence and collaboration. Individuals working alone made few of the major discoveries.

Rather than attempting to incorporate more scientific developments in this introduction, it seemed appropriate to place details in the Timeline, and in the annotations to the individual items in the collection. Based on citations to primary manuscript and printed sources, many of which are in the collection, and supported by standard reference works cited in the bibliography at the end of the catalogue, the timeline is carefully tailored to the work of the scientists who figure prominently in this collection. It attempts to show the chronology of discoveries and publications. While it does not pretend to be a history, or even a complete listing of key papers, it does briefly outline the development of major discoveries reflected in the collection. It also shows how a small group of men and women, many of whose papers are collected here, nearly all working at three small research centers in England, made discoveries that changed the world. Prepared with the sale of the collection in mind, and the space limitations of a sale catalogue, it should not be viewed either as a complete timeline or as thorough coverage of the vast documentation of complex ideas in this collection. As the old saying goes, it “barely scratches the surface.”

People who figure prominently in this collection made some of the most significant discoveries in the history of molecular biology. Sir Lawrence Bragg discovered X-ray analysis in 1912-13. Bragg’s students, Max Perutz and J. D. Bernal, and Dorothy Hodgkin, a student of Bernal, pioneered in the application of X-ray analysis to biological substances beginning in the late 1930s.

After World War II a new crop of researchers joined the earliest pioneers in England. This second generation of researchers on the structure and function of biological molecules included Francis Crick, Maurice Wilkins, Herbert Wilson, John Kendrew, Rosalind Franklin, and the American, James D. Watson, as well as the Norwegian, Sven Furberg. Their research on molecular biology took place in three locations: at the MRC Unit at the Cavendish Laboratory at Cambridge under Sir Lawrence Bragg and Max Perutz; at King’s College, London, and Birkbeck College, London, under J. D. Bernal.

Furberg, who was the first to determine the correct structure of a nucleotide, and the first to propose a helical structure for DNA, also created the first molecular models of DNA. He made the crucial observation that the sugars are at a right angle to the bases, a key element in the discovery of the double helix. Furberg did all his research on DNA at Birkbeck before returning to Norway.

Francis Crick was a doctoral student at Cambridge, researching hemoglobin under the supervision of Max Perutz, when he and Watson, also at Cambridge, discovered the double helix. In their first paper on the double helix Watson and Crick cited Furberg’s pioneering work. John Kendrew was a doctoral student of Perutz. Sydney Brenner joined the MRC Unit at the Cavendish in 1956. Wilkins, Wilson, and Franklin were at University College, London. Uncomfortable in the King’s College research environment, Franklin moved to Birkbeck in 1953. One of the most significant conclusions to draw from the timeline is the great historic significance of the researches of Rosalind Franklin on the structure of DNA and the tobacco mosaic virus (TMV).

After completing his PhD in physics at Cambridge in 1952, Aaron Klug joined Franklin’s team at Birkbeck in 1953, working with her until her death. He remained at Birkbeck until he returned to Cambridge in 1962 when the MRC Unit at the Cavendish was expanded into the MRC Molecular Biology Laboratory under the direction of Max Perutz. Eventually Klug became director of the laboratory. Klug’s work has been of major historical significance in seven areas of “structural” molecular biology:

The structure and assembly of tobacco mosaic virus (TMV). The TMV particle was the first macromolecular structure to be shown to self-assemble in vitro, allowing detailed studies of the mechanism. This research, begun under the direction of Rosalind Franklin, may be the most detailed system of its kind that has been worked out. (1950s through 1979)

The architecture of spherical viruses (1957-68)

3-D Image reconstruction in electron microscopy (the invention of digital image processing; 1966-68)

The structure of chromatin and the nucleosome (1977-84)

Transfer RNA (1974) and catalytic RNA (ribozyme) (1995-96)

Zinc fingers (1985-2001)

The structure”s” of DNA (1979-89).

The Klug and Perutz papers include correspondence with most significant researchers of the classical period of molecular biology. Written in the days before telephone replaced letters for serious communication, and before the invention of email, several of these correspondences consist of dozens or more of very detailed scientific letters written over decades. Some of the most notable among many are the letters between Perutz and Bragg and Hodgkin, and those of Klug with Crick and Donald Caspar. As records of collaborations between figures prominent in the foundation of molecular biology, these correspondences, dense with information, and often gracefully written, are invaluable documentation for the development of scientific thought. Of the scientists mentioned, Bragg, Watson, Crick, Wilkins, Perutz, Kendrew, Hodgkin, Klug and Brenner received the Nobel Prize.

Within the Timeline, and the collection itself, we see the repercussions of Watson’s controversial book on the key players, nearly all of whom strongly objected to details of Watson’s original draft, about ten copies of which were circulated among those who played major roles in the discoveries. These drafts had the working title of Honest Jim, a nickname for Watson. We see the objections of Crick and Wilkins, and the impact on Perutz’s career when it became known from Watson’s book that Perutz had shared a summary report of Rosalind Franklin’s researches with Watson and Crick. Watson’s controversial characterization, or mischaracterization, of the deceased Rosalind Franklin contributed to the legend that has grown around the life and work of this great scientist who died of ovarian cancer in 1958 at the age of only 37. The original Rosalind Franklin material in this collection is approximately equal in quantity and quality to the other primary archive of her scientific papers at Churchill College, Cambridge.

Having read Watson’s The Double Helix when it was originally published, and having later read other classic accounts of the history of molecular biology, including Robert Olby’s The Path to the Double Helix (1974), and Horace Judson’s The Eighth Day of Creation. Makers of the Revolution in Biology (1996), I could not resist the unique opportunity that occurred in the late 1990s to collect original manuscripts, correspondence and other documentation of epochal discoveries described in these histories and other works—discoveries that have transformed our view of life. In association with Christies I am pleased to offer this collection to the world on the fiftieth anniversary of the publication of the discovery of the double helix by Watson, Crick, Wilkins, Wilson, Franklin, Gosling and their colleagues. My special thanks to the staff of Christie’s Book Department in New York and to Jane Flower, archives specialist at Christie’s London, for preparing this collection for sale.