The Nature of the Intermolecular Forces Operative in Biological Processes, 1940

Linus Pauling, Max Delbrück and Max Perutz at the American Chemical Society centennial meeting, New York. April 6, 1976.

In 1940 Linus Pauling, along with colleague Max Delbrück, authored a three-page article that was published in the July issue of the journal Science. The length of the article was shorter than typical for Pauling, but what made it even more unusual was that it was not about Pauling’s findings. Instead, the piece served as a critique of a different article published earlier that year by a German scientist, Pascual Jordan.

In it, Jordan argued that when like molecules bonded, they were attracted more strongly than when dissimilar molecules bonded. Jordan believed that this stronger attraction of like molecules conferred special properties to these bonds, especially when they occurred in living cells. Pauling and Delbrück totally disagreed with this idea. Instead, the duo believed that it was a molecule’s complementary nature that conferred stability, an idea in opposition to Jordan’s concept of similarity.

In the two decades preceding these papers, chemists had come to look at their field in different ways, due mainly to advancements in quantum mechanics. This was certainly true for Pauling, who rapidly developed a reputation for using these new ideas to solve old problems. One line that he did not cross however, was the application of quantum mechanics to help “solve” topics that were already well understood and not in conflict.

For Pauling, one such instance was the basis of molecular attraction, and how that attraction created stability in a newly formed molecule. This idea, however, was something that other scientists found worth examining; Pascual Jordan in particular. Accordingly, and armed with a new set of quantum mechanical theories, Jordan set about attacking a question that others, including Pauling, believed not in need of answering.

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Pascual Jordan

Pascual Jordan was born in Germany in 1902 of Spanish lineage. Though initially interested in the arts, Jordan studied math and physics in school, completing his physics Ph.D. in 1924. His ideas at this time were novel, with no less a figure than Albert Einstein taking note of his dissertation. But Einstein did not agree with certain of the hypotheses that Jordan was putting forth, many of which used quantum mechanics to consider the photon nature of light. While Einstein felt that there wasn’t necessarily anything wrong with Jordan’s ideas, he did not agree with the logic that informed them, and wrote missives in opposition.

But others supported Jordan’s work and, soon after graduation, he began working with a circle of colleagues that included Werner Heisenberg. During this time, Jordan became one of the biggest proponents of quantum mechanics and, along with Heisenberg, helped to unlock many of its secrets. Jordan was also a member of the Nazi party, joining when Germany entered World War II and remaining so until at least the end of the war. Nonetheless, Jordan helped to develop key theories in physics and math which are foundational to the fields today.

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Though Jordan’s legacy today is marred by his political positions, when he wrote his 1940 paper about the attraction of molecules in biological cells, he did so from a position of authority. As noted, the foundation of the paper is the idea that identical molecules are attracted to one another in a special way that does not exist for dissimilar molecules and that, because of this, the bonds formed in molecules are more stable than is the case with other bonds. Jordan’s hypothesis, if true, would have been groundbreaking and consequential for all sorts of bonds, especially those in living cells.

Understandably, the paper created a lot of commotion when it was published. Pauling, who at that point was also an authority on quantum mechanics and resonance theory, was no doubt among those surprised by Jordan’s proposition. After reading it though, he immediately saw its flaws. In it, Jordan himself admitted some doubt that resonance could work in the manner that he was suggesting, and Pauling was sure that the ideas were wrong. Wishing to publish a rejoinder, Pauling began looking for a co-author whose expertise centered around bonds in living cells, and Max Delbrück was just such a figure.

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Like Jordan, Delbrück was born in Germany in 1906. Interested in the stars, Delbrück began his studies in astrophysics, but changed directions upon meeting a physical chemist, Karl Bonhoeffer, who was eight years his elder. Fascinated by Bonhoeffer, Delbrück switched to physical chemistry in a ploy to become his friend, a tactic that ultimately worked well. The timing of the switch was also fortuitous as Delbrück entered the field at the beginning of the quantum revolution. After graduation, Delbrück studied all over Europe with scientists included Wolfgang Pauli and Niels Bohr. He eventually spent a few years at the California Institute of Technology on a Rockefeller Foundation fellowship, during which time he met Pauling and co-authored the 1940 paper. After leaving Caltech, Delbrück focused his research on bacteriophages and eventually won the 1969 Nobel Prize in Physiology or Medicine for this work. 

Even though Delbrück’s Nobel honor was nearly thirty years down the road, by 1940 he was already well-versed on the ways that living cells operated, making him a formidable writing companion. In their paper, Pauling and Delbrück argued that Jordan’s fundamental idea could not be correct because the stability of a molecule was conferred by the complementarity its components, not their similarity. By way of explanation, the duo first put forth the understanding that a stable molecule is one in which molecular distances are relatively short. This is a circumstance, they argued, that can best be achieved when complementary forces are working together, such as positive ions attracting negative ions. In other words, in a bonding pair “the two molecules must have complementary surfaces, like die and coin.” The like molecules that Jordan was advocating for were not complementary by definition; rather, they were identical, or close to it. Pauling and Delbrück acknowledged that “the case might occur in which the two complementary structures happen to be identical” but still their stability “would be due to their complementariness rather than their identity.”

Even though Pauling and Delbrück’s article was quite short, its message was clear: Jordan was plainly wrong. As they wrote, “We have reached the conclusion that the theory can not be applied in the ways indicated by him [Jordan], and his explanations of biological phenomena on this basis can not be accepted.” In short order, the scientific mainstream came to agree with their point of view, and Jordan’s ideas soon faded away.

Campbell, Pressman, Pauling and the Binding of Antibodies

Drawings of the interaction between an antibody and azoprotein by Linus Pauling. 1940s.

Dan Campbell first collaborated with Linus Pauling on a fellowship at Caltech in 1940, during which time the duo tried to explain how antibodies are formed. At the time, Pauling believed that antibodies were proteins in-the-making that needed to bind to antigens in order to fold and complete their structure. If this principle was correct, Pauling thought, it might be possible to create artificial antibodies by simply denaturing proteins and allowing them to bind and refold in the presence of antigens.

Despite the fact that Campbell’s initial test results cast doubt on his collaborator’s theories, Pauling went ahead and published his ideas on how antibodies work, hoping that further research could support his paper. Thus began a lengthy study of antigen-antibody binding in which Pauling and Campbell attempted to develop a complete theory. Along the way, Dan Campbell’s research at Caltech would become very important to the Institute as well as to Pauling.

In 1943 a Caltech research fellow named David Pressman agreed to join Campbell and Pauling in their study of immunology. Starting with work that had previously been published, Pressman, Pauling and Campbell refocused their studies to explain how antigens and antibodies bind, a change in focus from Campbell and Pauling’s earlier inquiries into how antibodies and antigens are formed. The decision to focus on previous research was made after Pauling had mistakenly announced that antibodies had successfully been synthesized at the Gates and Crellin Laboratories. As it turned out, attempts to create synthetic antibodies using Pauling’s proposed methods were completely unsuccessful. Pauling thus decided to start from scratch by developing a theory of antigen-antibody binding, which he would use to further investigate the chemistry of this interaction.

In July 1943, the three men published “The Nature of the Forces Between Antigen and Antibody and of the Precipitation Reaction,” appearing in the journal Physiological Reviews. The paper attempted to make more educated predictions about antigen-antibody binding.  In doing so, the article begins by referencing the concept of structural complementarity, which posits that antigen-antibody binding is driven by the close complementary physical shapes of the two molecules, which fit together like two adjoining pieces in a jigsaw puzzle. Commonly referred to as “the lock and key mechanism,” this idea was developed in the early 1930s, and served as Pauling and Campbell’s starting point in their initial investigations.

The 1943 study also drew from outside theories, such as the framework theory of precipitation, to suggest that antigen-antibody binding results in the formation of a precipitate; that is, that the two structures react to form an insoluble compound. Using these points as their foundation, the three researchers developed a new theory of antigen-antibody binding.

Pauling and Campbell, 1943.

Campbell, Pressman and Pauling’s breakthrough came by way of their proposal that structural complementarity is an especially important feature for reactions that depend on Van der Waals forces. Van der Waals forces are weak forces of attraction that bind together molecules located in close proximity to one another. The Caltech researchers believed that the close complementary geometry of antibodies and antigens was significant enough to enable these molecules to fit together using the weak Van der Waals attraction as a binding force. In other words, the summation of Van der Waals forces present along the binding site of an antibody worked to bind it to its antigen, specifically because the shapes of antibodies and antigens complimented each other so closely. This theory explained much of what had been observed by immunologists across the discipline in multiple investigations of antigen-antibody reactions.

From here, the three researchers also asserted that two propositions placed forth in Pauling’s 1940 paper should still be considered for further study: the multivalence of antigen-antibody interactions and the probability of hydrogen bonds acting between the two molecules. The trio also concluded that the antigen-antibody mechanism would require at least two supplementary types of forces: Coulomb attraction and polar attraction.

Of the conclusions published by Campbell, Pressman and Pauling in 1943, the multivalence of antigen-antibody interactions and the three proposed forces (Van der Waals, Coulomb and polar) between the two molecules are still considered to be contributing factors to the functioning of the human immune system. With this publication, Campbell, Pauling and Pressman also showed that the immune system relies heavily on both structural and chemical features to carry out its processes.

The important conclusions derived from research conducted by Campbell, Pauling and others established Caltech as a leader in the field of immunology. Over the years that followed, Campbell and Pauling continued to develop their theory of antibody formation, which remained widely accepted until the 1950s. Even when the duo’s work began to be disproven by findings in the genetics field, the understanding of antigen-antibody interactions suggested by research done at Caltech remained undisputed.

Dan Campbell and Linus Pauling went on to publish more than twenty articles relating to immunology, exchanging ideas on the topic until the end of Pauling’s tenure at Caltech in the early 1960s. The attention that their work brought to the Gates and Crellin Laboratories at Caltech prompted the creation of a separate department, one that was entirely dedicated to immunochemistry. (The first of its kind on the west coast.)

For thirty years, Campbell headed Caltech’s immunochemical research and his fame as an immunologist grew to the point where, in 1972, he was named president of the American Association of Immunologists. Two years later, in 1974, Campbell passed away at the age of 67, the victim of a heart attack.  Over the course of his career, he published more than 200 papers as well as several books, and he served on editorial boards of four scientific journals related to immunology.