Marshall A. Lichtman
Rochester, New York, United States
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| Figure 1. The boyish appearing James Watson (left) and the Francis Crick with their three-dimensional model of DNA in their Cavendish Laboratory office at Cambridge University, United Kingdom. Circa 1953. Photo credit: A. Barrington Brown/Science Photo Library. Via the Rockefeller University Digital Commons. |
In the April 25, 1953 issue of the biomedical journal Nature, three articles were published on the structural characteristics of DNA. One was a three-dimensional model of DNA constructed by James Watson and Francis Crick of the Cavendish Laboratory, Cambridge University, who did no experiments to arrive at their conclusion. Their model was all based on their reasoning using the experimental studies of others to arrive at a unified whole; an accomplishment I do not minimize!
The prior 100 years of research included the discovery in the mid-nineteenth century of a chemical isolated from the nucleus of inflammatory cells, called nuclein and later renamed nucleic acid, different from protein and heretofore unknown. Nuclein was soon thereafter found in salmon sperm. Subsequently, it was determined that nucleic acid was made up of ribose sugar, phosphate, and nucleic acid bases. Thereafter, a determination was made that the nucleic acid bases in desoxyribose nucleic acid (DNA) were cytosine (C), guanine (G), adenine (A), and thymidine (T), and later that the ratio of each doublet of C-G and A-T was one to one, regardless the source of DNA from any cell type or organism. This finding strongly implied they were paired.
Until the mid-1940s, a body of scientific opinion felt that the genetic information held in chromosomes, composed of protein and nucleic acid, was more likely to be in the protein fraction. The variation in functions and number of proteins in humans is so great (hundreds of thousands), it seemed likely they would be best adapted to such a function. In 1944, an experiment established that DNA was the transforming factor that converted the phenotype of a non-virulent bacterial strain to a virulent phenotype. This finding was later confirmed using a different experimental model. These observations made it clear to the nay-sayers that DNA was the portion of chromosomes that carried genetic information and propelled the search for its structure, so as to better understand its function.
The second paper in the April 25, 1953 issue of Nature was that of Rosalind Franklin and a graduate student in her laboratory, and the third paper was that of Maurice Wilkins and two others in his laboratory, both working at Kings College, London. Franklin and Wilkins were applying x-ray crystallography to the question of DNA structure. This technique permits a monochromatic beam of x-rays to hit a crystalline specimen and the pattern of the reflected x-rays is observed on a detector. The character of the x-ray diffraction pattern can give important insights into the structural features of the sample under study, in this case DNA. The size and nature of DNA required pioneering adaptations of crystallography to accomplish the task. Franklin’s work was notable for her modifications to the technique that permitted original insights into DNA structure.
Watson, Crick, and Wilkins shared the Nobel Prize in Physiology or Medicine in 1962 for deciphering the structure of DNA nearly a decade after their publication. In part, this was related to challenges to the model’s accuracy, soon shown to be unfounded. The three were nominated for the prize in 1960, 1961, and 1962. The nomination by some was for the Nobel Prize in Chemistry and by some for the Nobel Prize in Physiology or Medicine. This conundrum was settled by the Nobel Committees, which decided that the structure was so important to biology to award the three scientists the Prize in Physiology or Medicine. The paper of Watson and Crick in Nature can arguably be considered among the three most important in the biological sciences. (The second, a monumental treatise, was Charles Darwin’s observations from his five-year expedition on HMS Beagle, exploring the nature of speciation, detailed in his monograph, On the Origin of Species by Means of Natural Selection, published in 1859. The third was Gregor Mendel’s description of the quantitative nature of the transmission of hereditary traits in generations of pea plants, circa 1866, defining dominant and recessive inheritance and other features of what became known as Mendelian genetics.)
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| Figure 2. The commemorative 50 pence coin released by the Royal Mint on July 25, 2020, the 100th anniversary of Rosalind Franklin’s death. It has a replica of a portion of Franklin’s photograph 51, showing a rough facsimile of the x-ray diffraction pattern of DNA, critical to deciphering the structure of DNA, and Franklin’s name. Note, her name vertically ends in D and N and the engraver added an A to their right to make the horizontal “DNA”. Queen Elizabeth II’s profile is on the other side of the coin. Designed by David Knapton. Via The Royal Mint. |
Remarkably, as a testimony to the elegance of the molecule, DNA, and to the incisiveness of the scientists, Crick’s and Watson’s Nobel Prize winning paper in Nature was one page long and had no laboratory experiments of their own. Crick, initially studying physics, had not yet earned his Ph.D. and had little background in biology, organic chemistry, or crystallography, which he learned at Cambridge working in the laboratory of Max Perutz starting in 1947 as he turned from physics to biology. Watson, aged twenty-five in 1953, was two years out from his one post-doctoral year at the time of publication of the Nature article. (Figure 1.) Their work took but two years to complete. This was an extraordinary basis for the award of the Nobel Prize in Physiology or Medicine, indeed uniquely so, but they asked the most important question in biology and answered it rather quickly!
Almost a decade elapsed between the report of the structure of DNA (1953) and the Nobel Prize for its discovery (1962). This was a surprising interval, given the significance of that molecular structure and its centrality to understanding how genetic information is stored and transmitted. As another example, Peyton Rous, working at the Rockefeller Institute, won the Nobel Prize in Physiology or Medicine for his research on a putative avian cancer virus in 1966 at age eighty-eight. These studies were prompted by a farmer bringing him a hen with a tumor and asking him to explain the abnormality. The Nobel Prize was awarded fifty-five years after his two publications on the discovery of a transmissible agent as the cause of a sarcoma in fowls in 1911, later dubbed the Rous Sarcoma Virus. It took that long to recognize its importance in cancer biology.
Alfred Nobel’s will stipulated that the prizes should be given to the person who made the greatest contribution to humankind in each of the prize categories in the preceding year. This stipulation was wisely overlooked by the Nobel Foundation. Rous began his Nobel lecture with this sentence, “Tumors destroy man in a unique and appalling way, as flesh of his own flesh which has somehow been rendered proliferative, rampant, predatory and ungovernable.” His lecture, although more than a half-century ago, is a remarkable qualitative prediction of the nature of cancer and had the same literary tone as the first sentence. His descriptions have since been defined in genetic and molecular terms.
Franklin, whose findings were critical to Watson and Crick’s model, died of ovarian carcinoma at age thirty-seven in 1958. (She probably had a germline BRCA mutation, prevalent in Ashkenazi Jewish women. Cancer developing at age thirty-five makes a BRCA mutation likely.) Nobel Prizes are not given posthumously, nor are more than three persons allowed to share a Prize. Much has been written about the misogyny and the disparate personalities that existed between Watson and Franklin or between Wilkins and Franklin that played into Franklin’s isolation. Many have argued that any fair reading of the history of the discovery of the structure of DNA had to conclude that Franklin was profoundly wronged. Watson and Crick initially considered a model that was wrong. She (among others) told them what was wrong. They had the phosphates pointing inward and the nucleic acid bases pointing outward. She was an excellent chemist, they were not. She explained that the hydrophilic phosphates must point outward and the hydrophobic nucleic acid bases must point inward. In her famous X-ray crystallographic image (photograph 51), she established that the DNA molecule was a double helix, a revelation that went a long way to solving its structure. The image was taken by Wilkins from Franklin’s papers and was shown to Watson and Crick before she published it and without her knowledge. It gave Watson a eureka moment. Since the nominations were after Franklin’s death, she was not eligible, but her failure to be nominated before her death from 1953 to 1957 along with Crick and Watson was a remarkable oversight. Her prior and subsequent research, the latter on viruses, was impactful as well. Indeed, she could have been considered for a Nobel Prize for contributions to delineating virus structure had she lived a longer life. She has to be considered one of the preeminent scientists of her era. The Royal Mint released a commemorative 50 pence coin imprinted with her name and an image of photograph 51 showing the helical structure of DNA by x-ray crystallography, on what would have been her 100th birthday, July 25, 2020. (Figure 2.) It is the second coin in the Royal Mint’s “Innovation in Science series,” the first being dedicated to Stephen Hawking.
A short time before Watson and Crick submitted their paper to Nature, on March 19, 1953, Crick sent his son, then at a British boarding school, a seven-page handwritten letter excitedly and explicitly describing their finding. It began “My Dear Michael, Jim Watson and I have probably made a most important discovery . . .” In the letter, there were four hand-drawn sketches of (i) the linear structure of DNA, (ii) the helical structure of DNA, (iii) a diagram of specific base pairing (C with G and A with T), and a drawing of how the two DNA strands separate and are replicated so as to pass on the genetic information. The end of the letter read “Read this carefully so that you will understand it. When you come home we will show you the model. Lots of love, Daddy.” In effect, this was the first document released from their laboratory describing the structure of DNA. A link to a facsimile of the hand-written letter is available here.
Francis Crick died in 2004 at age eighty-eight. Nine years later, Crick’s heirs, including Michael Crick, decided to sell eleven of Crick’s scientific artifacts to support medical research. These included Crick’s Nobel Prize gold medal, a laboratory notebook, his stained laboratory coat, and an endorsed Nobel Prize check in Swedish krona, dated December 10, 1962. December 10 is the date of Alfred Nobel’s death and the date on which the Prizes are awarded in Stockholm. Most of the proceeds from the sales were donated to the Salk Institute for Biological Studies in La Jolla, California, where Crick had been faculty later in his career, and to the future Francis Crick Research Institute in London, established in 2010 and opened in 2016. Thus, sixty years after the letter was written and the historic paper was published, the Crick family put the letter up for auction at Christie’s New York with an asking estimate of about one million dollars. The letter was sold to an anonymous buyer for 5.3 million dollars and with fees the sale came to $6,059,750, the largest amount ever paid for a letter at an auction. (The prior highest price, 3.4 million dollars, was for a letter written by Abraham Lincoln in 1864 in response to a petition by 195 boys and girls asking Lincoln to free slave children. Although the Emancipation Proclamation was issued in 1863, the slaves were not freed until the thirteenth Amendment to the Constitution was passed in 1865.) Crick’s twenty-three-carat-gold Nobel medal sold at auction for 2.27 million dollars to an American businessman of Chinese descent.
One can conjecture about hand-written letters of great historic importance being discovered unexpectedly in a cardboard box in the loft of an antique barn. This has happened, but such a serendipitous event is unlikely in the future. It has been replaced by the image of searching many floppy disks and finding an email or a typed attachment to an email, signed digitally, for a document of extraordinary historic consequence: a less agreeable experience. More distressing is that artificial intelligence is being used for letter writing. Thus, the digital letter may not represent the thoughts of the author.
References
- Dahm R. Frederick Miescher and the discovery of DNA. Develp Biol 2005;278 (2):274-288.
- Rosalind Franklin. The dark lady of DNA. Brenda Maddox. HarperCollins Publisher, New York. 2002.
- Lichtman MA. Alfred Nobel and his prizes. From dynamite to DNA. Rambam Maimonides Med J 2017, July;8(3) e0335 doi: 10.504/RMMJ.10311
MARSHALL A. LICHTMAN, M.D., M.A.C.P., is Professor Emeritus of Medicine and of Biochemistry and Biophysics and Dean Emeritus of the University of Rochester School of Medicine and Dentistry. In 2017 he received the Wallace H. Coulter Award for Lifetime Achievement in Hematology from the American Society of Hematology.
Highlighted in Frontispiece Volume 12, Issue 4 – Fall 2020
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