Pauling’s Theory of Sickle Cell Anemia

It's in the BloodWe owe to Pauling and his collaborators the realization that sickle cell anaemia is an example of an inherited ‘molecular disease’ and that it is due to an alteration in the structure of a large protein molecule, an alteration leading to a protein which is by all criteria still a haemoglobin.
- Vernon M. Ingram, 1957.

Of the four Documentary History websites that the OSU Libraries Special Collections has produced, “It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia” is, in certain respects, the most unique.

For one, “the blood site” — its usual in-house appellation — is the only of our Documentary Histories not to have been written by Pauling biographer Tom Hager.  On the contrary, the idea for the blood site arose out of a history of science master’s thesis that Melinda Gormley — then a graduate student and now a professor at OSU — developed from research done in the Ava Helen and Linus Pauling Papers. As Dr. Gormley documented in this article (PDF, see pp. 8-9) it took the better part of two years to repurpose the text of her dissertation into a format suitable for the web.

Gormley’s thesis topic was relatively broad — “The Varieties of Linus Pauling’s Work on Hemoglobin and Sickle Cell Anemia,” (PDF, 1.8 MB) — and, as a result, the swath of content covered in the website is similarly wide.  The website begins its narrative in 1930, ends it in 1994, and along the way discusses Pauling’s contributions to areas ranging from immunology to Scientific War Work to evolutionary theory to orthomolecular psychiatry.  All of these topics will be addressed in future posts on this blog.

The heart of the blood site, however, is Pauling’s research on sickle cell anemia. Sickle cell anemia is a terrible disease that predominantly effects inhabitants of sub-Saharan Africa or those who can trace their lineage to that region.  The disease is a painful one, characterized by drastically-malformed red blood cells, and manifesting itself in a host of health maladies and, often, shortened lifespans.

Many folks who are semi-acquainted with the Pauling legacy know that he was, in some way, important to the modern understanding of sickle cell anemia.  But how? Well, Linus Pauling was the first individual to correctly theorize that sickle cell anemia is a disease that locates its source to the molecular level — in the process Pauling likewise became the first individual to postulate the concept of a molecular disease.

What then, exactly, was Pauling’s theory of sickle cell anemia?  That is the question that we aim to explore in this post.

Linus Pauling probably wasn’t a true freak-of-nature genius in the manner of an Einstein or a Mozart.  On the contrary, the likely secret of his profound success as a scientist was at least threefold in nature: 1) he possessed a relentless work ethic; 2) he was a very clear and concise thinker who conceptualized his ideas well and understood the efficiencies inherent to leading teams of researchers as opposed to going it alone; 3) and most importantly, he was deeply interested in, and capable of concretely understanding, radically-disparate areas of scientific study.  All three of these traits reveal themselves in the sickle cell anemia story.

Pauling first encountered the problem of sickle cell anemia rather by accident.  At a dinner in 1945, Pauling sat in the audience of an informal presentation by physician Dr. William Castle, wherein it was noted that the shape of red blood cells in sickle cell patients varied depending on whether the blood was venous or arterial –  normal in arterial blood, sickled in venous blood.  Clearly this suggested that the oxygen content in sickle cell blood played a major role in its molecular architecture. By his own recollection, “within two seconds,” Pauling concluded that the oxygen piece of the equation suggested that hemoglobin must be involved in the sickling mechanism — a conclusion that he could reach because of his keen understanding of the structural chemistry of hemoglobin.

In 1960, Pauling provided this description of his initial thoughts on how malformed hemoglobin could lead to sickled red blood cells.

…immediately I thought, “could it be possible that this disease, which seems to be a disease of the red cell because the red cells in the patients are twisted out of shape, could really be a disease of the hemoglobin molecule?” Nobody had ever suggested that there could be molecular diseases before, but this idea popped into my head. I thought, “could it be that these patients can manufacture a special kind of hemoglobin such that the molecules are sticky and clamp on to one another to form long rods, which then line up side by side to form a long needle-like crystal, which as it grows inside of the red cell becomes longer than the diameter of the cell and thus twists the red cell out of shape?”

A sickled red blood cell

A sickled red blood cell

From here, Pauling delegated many of the details necessary to verifying his thinking on the sickle cell problem to a team of Caltech graduate students led by Harvey Itano.  (This was common practice for Pauling, and helps explain how he was able to generate over 1,100 published papers in ninety-three years of living)  Using a variety of methods including electrophoresis, the Itano team, in the words of a 1950 Caltech press release

found a difference – slight but still unmistakable – between normal hemoglobin and that of a sickle-cell anemia patient.  Sickle-cell hemoglobin proved to have a greater positive electrical charge, under the proper chemical conditions, than did the hemoglobin from a normal person.  Such a difference in electrical properties can only mean a difference in molecular architecture, in the way in which the hemoglobin molecules are constructed.

In other words, Pauling was right: sickle cell anemia was a molecular disease and malformed hemoglobin was the cause.

In 1956, an English chemist named Vernon Ingram, using a new technique called fingerprinting, (Pauling provides a rather technical description of the method here) proved conclusively that sickle cell anemia was an inherited disease as well.  Moreover, sickle cell anemia was found to be caused by an astonishingly small change at the molecular level.  Physicist John Hopfield described it this way

On the surface of the ten-thousand atom molecule, there is a slight change. A small group of a few atoms on the edge of the molecule is replaced by another small group of atoms. That’s all that happens – an exchange of a few atoms. Yet it’s enough to make people very ill. The effect of the change is to create a sticky point between an abnormal molecule and its neighbor, causing molecules to pile up on each other.

Just as Linus Pauling predicted, after dinner, in 1945.

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5 Responses

  1. Thanks for the information. I read about it and that doctors are trying to help children with bone marrow transplants. Hope the treatment process works for them. This is the site click here SICKLE CELL CURE

  2. [...] Tour of the OSU Libraries Special CollectionsFeatured Document: Linus Pauling’s Birth CertificatePauling’s Theory of Sickle Cell AnemiaThe Heisenberg Uncertainty PrincipleRoger Hayward (1899-1979): The Western Years, Part 1Roger [...]

  3. i am a master’s degree student of microbiology from Nepal. i’ve been writing a review article on “Sickle Cell Anemia” and this site has been very helpful for me,. thanks

  4. [...] most important immunological discoveries were his elucidation of the role that hemoglobin plays in sickle cell anemia and his theory of antibody formation.  The latter is the topic of today’s [...]

  5. I m a final year student nurse from school of nursing katsina nigeria. I m writng a research study on sickle cell anaemia and i read this where i got much. Tnkx

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