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  • Writer's pictureH. Paul Putman III, MD

Shoulders of Giants: Theoretical Biology

Updated: Sep 2, 2021

Question: How many experiments did James Watson and Francis Crick perform to determine the structure of deoxyribonucleic acid (DNA)? Answer: None, not one.

Actually, this esteemed pair did rely upon experiments that were performed by others, without which neither scientist would have had sufficient information to determine DNA's structure. Most notably these included Rosalind Franklin and Maurice Wilkins' X-ray crystallography results that suggested a helical shape, Alexander Todd's determination of the backbone constituents of repeating phosphate and deoxyribose groups, Edwin Chargaff's discovery that in each species the amount of adenine always matched that of guanine with a similar correspondence for cytosine and thymine, and Jerry Donohue's advice on atomic ring configuration (NLM 2020). What is nevertheless remarkable, however, is that Watson and Crick elucidated the structure, performing a thought experiment with available data and changing the worlds of Biology and Medicine forever.

They functioned much as theoretical physicists do, who use mathematical calculation based on available evidence to propose hypotheses that experimental physicists might then be able to confirm. One need only follow the popular press to learn every year or so that yet another of Einstein's theories has been supported or disproven, mostly the former. In fact, while Watson and Crick's paper, published April 25, 1953 in Nature, proposed a rational structure for DNA, and matched the base pairs adenine-thymine and guanine-cytosine, it only proposed that perhaps the genetic message might actually be embedded in the pattern of these pairings. They provided no data at that time that it actually was.

Much of molecular biologic research for the last century has been "wet lab" - actual physical experiments based on hypotheses. But how many significant breakthroughs in Biology have been theoretical? That is the beauty of Watson and Crick's 1953 one-page paper - it is elucidation, not experimentation. In the history of life sciences, one can really only point to Charles Darwin as offering similar elucidation, based upon observation of data, that changed the world.

This is not at all a plea to abandon experimentation - it is the basis upon which we must rest the scientific method. Gregor Mendel performed experiments, as did Louis Pasteur and Edward Jenner and we are grateful that they did. All theories must be subjected to the best designed and most rigorous tests and rational statistical analysis. And yet, all experiments must begin with a hypothesis.

In Biology, we pretty much rely upon experimental biologists to provide their own theories, while in Physics, a clearer distinction exists between theoretical and experimental scientists and much continues to be gained by such an approach. It is probable that this division of labor is made necessary by the extreme sophistication a theoretical physicist must have with mathematics. Such is increasingly necessary in Computational Biology: as it grows into a more mature field of its own, we may be seeing a similar dichotomy develop in the life sciences, including Medicine, where key understandings from the manipulation of existing data may provide the key breakthroughs that can then be confirmed. Analysis of Big Data and tools not even yet conceived of will likely add to the ability of bright minds to advance life science without relying solely on wet-lab expertise. This two-pronged, rather than singular approach, will likely accelerate our progress. Our thanks to Darwin, Watson and Crick for elucidating the way.

Reference: National Library of Medicine (NLM), "The Discovery of the Double Helix, 1951-1953. Available at, accessed May 31, 2020.

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