The Slow March Toward a Cure for Sickle Cell Disease

Pastel drawing of sickled hemoglobin cells by Roger Hayward, 1964

By Dr. Marcus Calkins

[Ed Note: This is the first of three posts examining the history of sickle cell treatment up to present day. It is authored by Marcus J. Calkins, Ph.D., “a proud OSU alumnus” (Chemical Engineering, B.S., 1999), who now works as a scientific communications service provider and educator in Taipei, Taiwan. In submitting this piece, Calkins emphasized that he has “taken inspiration from Linus Pauling’s research activities, teaching methods and moral character for many years.”]

In 2020, Jennifer Doudna and Emmanuelle Charpentier shared a Nobel Prize for their discovery and development of the CRISPR gene editor. One of the first clinical applications for CRISPR promises to be an ex vivo gene therapy for Sickle cell anemia. If it works, this medical technology will be a major breakthrough in biomedicine, representing the culmination of more than a century of research on Sickle cell disease that encompasses a wide range of topics.

Despite the lifetimes of work that have led to our current exciting position on the precipice of a cure for Sickle cell disease, the basic molecular features of the disease were defined seven decades ago by another Nobel Prize winner, Linus Pauling. The intervening 70 years of work have been required for scientists to learn how we might apply the foundational knowledge to actual patients in a real-life clinical setting. While the pace of progress may seem agonizingly slow to those outside biomedical research, the ground that has been covered is immense, and entire fields of biomedicine needed to be built and optimized before a truly feasible treatment technology could be invented.

Sickle Cell Disease (1910)

Sickle cell disease was first described over the period from 1910 to about 1924. During this time, a series of case reports detailed approximately 80 people of African descent, who had an odd morphology of red blood cells resembling a crescent or a sickle. In many cases, this sickle-like morphology was associated with a devastating condition involving severe anemia and early death. Furthermore, scientists learned that the red blood cell sickling could be exacerbated by depriving the blood of oxygen, either by adding carbon dioxide to cells in a dish or restricting blood flow in the patient. These clinical observations laid the foundation for basic scientists to postulate that the condition was related to hemoglobin, the protein that carries oxygen in red blood cells.

The first person to make this suggestion was Pauling. At some time in 1945, he was chatting with a colleague on the train from Denver to Chicago, when he learned about the difference in sickling between oxygenated and deoxygenated blood. According to the account of his colleague, Pauling was also informed that the sickled red blood cells show birefringence when viewed under a polarizing microscope, which would suggest an alignment of molecules within the cells.

However, by Pauling’s account of the conversation, his immediate guess that Sickle cell disease is caused by a defect in the hemoglobin protein complex was based entirely on the difference in the sickling properties of oxygenated and deoxygenated blood. Notably, Pauling later stated that the idea of Sickle cell disease being singularly caused by the hemoglobin molecule came to him in “two seconds,” but gathering evidence and refinement of the idea took at least three years.

In his public talks, Pauling often emphasized the fact that in the first years of the study, his students performed many experiments but could not identify any obvious biochemical differences between the hemoglobin molecules of patients and control individuals. From his repeated emphasis of this fact, one might speculate that the translation of a two-second idea to a three- or four-year demonstration would have been frustrating for such a quick-minded individual, though Pauling never said as much. Alternatively, he may have simply been emphasizing the challenges and slow, steady nature of rigorous scientific pursuit.

The Molecular Defect and a Potential Cure (1949)

In 1949, prior to the double helix model of DNA and before stem cells were described, the Pauling lab published a paper titled “Sickle Cell Anemia, a Molecular Disease.” In this work, Pauling and his students definitively showed that a slightly abnormal form of hemoglobin is found exclusively in patients with the cell sickling phenotype. Using a 30-foot-long Tiselius apparatus that they had constructed for electrophoresis, a small two-electron difference could be detected in the overall charge of hemoglobin molecules from Sickle cell patients and unaffected individuals. Meanwhile, carriers of the disease had a mixture of the two hemoglobin isoforms.

Importantly, Pauling’s group found that the defect in hemoglobin is not related with its ability to bind oxygen. Instead, it was later shown that the slight change in molecular charge affects the way hemoglobin proteins interact with each other, as would be predicted from the birefringence observation. This aberrant interaction causes the formation of long molecular scaffolds that change the shape of the red blood cell and lead to its dysfunction.

With this publication, Sickle cell disease became the first disorder to be associated with a single molecule. It was also the first with a known genetic basis. In his publication of the same year, J.V. Neel showed that Sickle cell disease follows an autosomal recessive inheritance pattern, meaning that each parent must contribute one copy of the mutated gene for a child to develop the disease. The cell sickling phenotype can occur to some degree in people who only carry one mutant allele, but only those with two copies experience the pernicious effects of the disease. This information, combined with Pauling’s study, established the essential basis for our understanding of Sickle cell disease and serves as a model for many other genetic diseases.

Surprisingly, James Watson (prior to his famed work on the structure of DNA) contributed a prescient idea to Sickle cell disease treatment, when he speculated that cells could be protected by expression of another form of hemoglobin, fetal hemoglobin. Watson made this prediction in 1948, just one year before Pauling’s powerhouse publication. His suspicion was an extension of reports that red blood cell sickling did not happen in the blood of infants who would later develop the condition as children and adults.

The stage was thus set for a Sickle cell disease cure. After the theoretical basis was determined, onlookers might have expected a cure for the disease to be found within a few years. However, extension of the ideas of Pauling and Watson has required incredible efforts by myriad scientists over the course of the next seven decades to create a potential new clinical reality.

Pauling’s Receipt of the National Medal of Science

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Ava Helen and Linus Pauling at the White House with President Gerald Ford and other recipients of the National Medal of Science, September 18, 1975

On September 18, 1975, the determination of many sectors of the scientific community culminated in an early afternoon ceremony held in President Gerald Ford’s Oval Office. It was on this date that Linus Pauling at long last received the 1974 National Medal of Science, an award that was long in the coming.

Immediately after the news of his selection was announced, Pauling began to receive a steady stream of congratulatory letters from friends and colleagues. In many of these communications, Pauling’s scientific peers made reference to the long delay that had preceded Pauling’s receipt of the award. One suggested that “in my estimation you should have been the very first chemist to receive this recognition” and another opined that “this is an honor which, for you, is long past due.”

Permeating much of this dialogue was a common understanding as to the cause of the delay: namely that Pauling’s outspokenness on social and political issues had not been appreciated by high ranking officials of the U.S. government. As one correspondent put it

we know that you would have long ago received this honor if you had been silent during the Vietnam War and if you had not spoken out on every occasion in the interest of the people of the United States as a peace-loving nation.


 

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Tagged as a communist in the 1950s and scorned by many for the consistency of his anti-war point of view, Pauling was used to fighting for the recognition that he deserved, and the case of the National Medal of Science proved to be no exception.

Established in 1959, the National Medal of Science is the most prestigious honor bestowed upon scientists by the U.S. government. Pauling, who had made significant contributions to a staggering array of scientific disciplines by the late 1950s, was clearly a leading candidate for the medal from the moment of its inception. However, his vocal campaign against the perils of the nuclear age served to politicize the process by which he might have been considered for the award, the result being that others were chosen in his stead for fifteen years.

In the run-up to 1974, a growing controversy had built around Pauling’s lack of recognition by the White House. Though scientists on the President’s Committee for the National Science Award had persistently put forth Pauling’s name as a preferred choice, he was continually passed over. The controversy heightened once word began to circulate that President Richard Nixon had pointedly refused to grant Pauling the award not once, but twice.

Some two decades later, Pauling learned that Nixon had been so upset by the tenacity of the American Chemical Society and the American Crystallography Association – organizations that both refused to put forth any nominations other than Pauling – that he decided to forego conferring the award at all. And indeed, no scientists received the decoration in 1971 or 1972.

While certainly a slight against him personally and to the scientific community writ large, Nixon’s refusal to honor Pauling with the medal may have actually come as something of a relief. It is safe to say that Pauling’s relationship with Nixon was fraught with tension and mutual distaste to the point where a meeting between the two would have proven awkward. As Pauling would later point out in a reply to a congratulatory letter, “I am at least glad that it was delayed beyond the Nixon regime.”


The slights weren’t all coming from the nation’s capital. Closer to home, Pauling found himself in a tussle with a local paper, the Palo Alto Times, that had neglected to mention Pauling as being included in the membership of the class of 1974. Instead, in an edited United Press International story headlined “Stanford prof awarded national medal,” the paper focused on the achievements of Paul Flory, a recent Nobel laureate who was soon to retire from the Stanford faculty. A final paragraph listing all of the 1974 recipients did not include any reference to Pauling nor, to be fair, three other scientists who were to be likewise honored.

When he contacted the paper to complain and suggested that the publication’s omission had been “damaging” to him, Pauling was met with a rebuke: “The city editor said I was a great scientist but a lousy lawyer, and they would print the story how they wanted to.”

A similar situation played out with the San Francisco Chronicle, which ran a different story emphasizing two Bay Area scientists in the class – Flory and Ken Pitzer – but not Pauling. A subsequent follow-up with UPI confirmed to Pauling that his name had been included in the wire release issued by the news service to its regional offices.


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Many others shared a far more positive view of Pauling’s decoration. For some, President Ford’s decision to award Pauling with the National Medal of Science signified a welcome thawing of relations between scientists and the executive branch. As one newspaper editorial noted, “the withheld honors for the great scientist had come to symbolize a growing estrangement between the government and the scientific community.” In addressing this estrangement symbolically, Ford seemed to be indicating that a scientist could speak their mind without fear of penalty.

 

In remarks published in The Medical Tribune, James Neel – a fellow member of the 1974 award class – held up Pauling as a role model and suggested that the government’s recognition should serve as validation for all socially motivated scientists. In Neel’s estimation

[Pauling] personifies the best in the psyche of the scientist: he is interested in the way life functions and in keeping living things alive. His social views are thus an extension of his work and values as a scientist. His greater perception of the meaning of life is what gives significance to his ideas and resonance to his contributions.

Others, however, understood that Pauling’s road to the National Medal of Science had been rocky and offered private words of support. As biochemist Britton Chance, also a member of the class of 1974, noted

 

you may have had mixed feelings as to whether [the National Medal of Science] was worthy of your accomplishments….[but] you have had a really remarkable career, and as I hope you know, to my view you are truly the out-standing genius of our time.

By the time of his passing in 1994, Linus Pauling had received forty-seven honorary doctorates as well as essentially every award that a scientist in his fields of study could win. And though the theatrics surrounding his belated National Medal of Science award surely proved frustrating, one might posit that the commendation of peers like Britton Chance served as stronger validation for Pauling than did nearly all of the hundreds of medals, plaques and certificates that he received over the course of a hugely distinguished career.

 

 

 

 

 

 

 

 

Dr. Michael Kenny, Resident Scholar

Dr. Michael Kenny

Dr. Michael Kenny

Dr. Michael Kenny, emeritus professor in the Department of Sociology and Anthropology at Simon Fraser University, recently completed a term as Resident Scholar in the Oregon State University Libraries Special Collections and Archives Research Center. Kenny is the twenty-fourth individual to have conducted work at OSU under the auspices of this program.

Part of Kenny’s scholarly background is in the eugenics movement, and it is this prism that framed his interest in conducting research in the Pauling Papers. Kenny was specifically interested in investigating the changing cultural milieu in which Linus Pauling worked and the ways that this environment may have impacted Pauling’s thinking on issues associated with eugenics.

Kenny was likewise very keen to examine the rhetoric that Pauling used during the years in which the dangers of nuclear fallout were an item of active debate. As it turns out, much of this rhetoric assumed a tone similar to that used by eugenicists contemporary to Pauling. That said, with Pauling and certain of these contemporaries, the use of this rhetoric was not motivated by anything like the ideals that we now commonly associate with the eugenics movement of the early twentieth century.


Rockefeller Foundation administrator Warren Weaver.

Rockefeller Foundation administrator Warren Weaver.

In his research, Kenny leaned in part on a secondary source, Lily Kay’s The Molecular Vision of Life (1993), which examined the development of molecular biology at Caltech during its infancy in the 1930s. Pauling was a central figure in this important chapter of scientific history, having shifted his research program to focus on “the science of life” – specifically, the determination of various protein structures – as funded during the Depression years by the Rockefeller Foundation.

As Kay pointed out in her book, the Rockefeller Foundation harbored a pre-existing interest in eugenics which may have propelled its desire to fund work in the burgeoning field of molecular biology. Rockefeller administrator Warren Weaver, who was Pauling’s main contact with the funding organization, wrote specifically of the Foundation’s interest in exploring “social controls through biological understanding,” and himself considered molecular biology to be the “only way to sure understanding and rationalization of human behavior.”

In his correspondence with Pauling, Weaver likewise suggested that “you are well aware of our interests in the possible biological and medical applications of the research in question.” Queried about the Rockefeller Foundation’s interest in eugenics by Lily Kay in 1987, Pauling replied, “I do not have much to say here,” noting that “my own interest in medical chemistry resulted from my interest in molecular structure.”


James V. Neel

James V. Neel

One major outcome of Pauling’s research on protein structures was his discovery that sickle cell anemia is a molecular disease. This work was conducted in parallel to similar investigations carried out by the human geneticist James V. Neel, a major twentieth century scientist who discovered that sickled cells are the result of a heterozygous mutation that, when it becomes homozygous, leads to sickle cell disease.

For Kenny, James Neel provides a bridge of sorts in the scholarly analysis of Pauling. In addition to his work on sickle cell traits, Neel also was involved in ethnographic research on the indigenous Yanomami population in Brazil. This study was funded by the United States Atomic Energy Commission in the late 1950s and early 1960s, and was motivated by the U.S. government’s desire to more fully understand the consequences that atmospheric radiation might portend for the human gene pool.

The debate over radioactive fallout from nuclear weapons tests during this time was fierce and continually hamstrung by a lack of concrete data. Linus Pauling, of course, was a key figure in the debate, and as Kenny and others have pointed out, he and his opponents used essentially the same data to draw very different conclusions from one another. Indeed, both sides were effectively engaging in the politics of risk assessment in arguing over the likely genetic implications for future generations of radioactive fallout released into the atmosphere by the nuclear testing programs of the era.

Hermann Muller

Hermann Muller

In developing and espousing his strong anti-testing point of view, Pauling was heavily influenced by Hermann Muller, a Nobel Laureate geneticist who is perhaps best known for proving the mutagenic effects of x-rays on fruit flies. According to Kenny, Muller was pretty clearly a eugenicist who spoke often of the need to maintain the purity of the pool of human germ plasm.

For Muller, essentially all mutations caused by radiation were to be viewed as a negative. While he acknowledged that natural selection is indeed the result of mutations that occur over the course of time, Muller believed that an increase in the rate of mutation is very likely to result in negative consequences. In arguing this, Muller pointed out that many mutations are buried and do not emerge until specific reproductive combinations come to pass. As Pauling and James Neel showed in the 1940s, sickle cell anemia is one such situation where this is the case.

Kenny points out that Muller’s ideas are imprinted all over Pauling’s 1958 book, No More War!, and in this book, as well as in his speeches, Pauling frequently used language that drew upon that of Muller and other eugenicists of his time. “I believe that the nations of the world that are carrying out nuclear tests are sacrificing the lives of hundreds of thousands of people now living,” he wrote, “and of hundreds of thousands of unborn children. These sacrifices aren’t necessary.” On other occasions, Pauling more directly echoed Muller, arguing that “we are the custodians of the human race, we have the duty of protecting the pool of human germ plasm against willful damage.”


So given all of this, was Pauling a eugenicist? For Kenny, the answer is no, or at least not “an old fashioned eugenicist in any clear sense.” Rather, Kenny sees Pauling as being one of many transitional figures (fellow Peace laureate Andrei Sakharov is another) working along a historical continuum that exists between the eugenicists of the late 19th and early 20th centuries, and contemporary ideas including genetic counseling and genetic engineering.  One of the more intriguing quotes that Kenny uncovered was Pauling’s statement that

Natural selection is cruel and man has not outgrown it. The problem is not to be solved by increasing mutation rate and thus increasing the number of defective children born, but rather by finding some acceptable replacement for natural selection.

For Kenny, Pauling’s suggestion of a possible replacement for natural selection anticipated contemporary techniques that are now deployed to minimize or negate what would otherwise be devastating hereditary diseases in newborn children. For expectant parents currently opting in favor of genetic counseling, as for Pauling in his day, the goal is to minimize the amount of human suffering in the world, not by proscription or law, but by choice. This ambition, which is global and cosmopolitan in nature – and not dissimilar to contemporary activism concerning global climate change – stands in stark contrast to the racist or nationalist motivations that fueled the eugenics of a different era.

For more on the Resident Scholar Program at the OSU Libraries, see the program’s homepage.