Pauling, Zuckerkandl and the Molecular Clock

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Dr. Emile Zuckerkandl, 1986.

In 1963, a year after first publishing their ideas on the study of molecules as indicators of evolutionary patterns, Emile Zuckerkandl and Linus Pauling continued to explore what they felt to be a very promising thread of inquiry.

Specifically, the two joined in arguing that the molecular clock method – as they had since termed it – might be used to derive phylogenies (or evolutionary trees) from essentially any form of molecular information. This position was further explicated in “Molecules as Documents of Evolutionary History,” an article published in Problems of Evolutionary and Industrial Biochemistry, a volume compiled in 1964 on the occasion of Soviet biochemist Alexander Oparin’s 70th birthday.

Zuckerkandl and Pauling’s most influential work on this subject was first put forth that same year, in a paper that they presented together at the symposium “Evolving Genes and Proteins,” held at the Rutgers University Institute of Microbiology. The talk, formally published a year later and titled, “Evolutionary Divergence and Convergence at the Level of Informational Macromolecules,” classified molecules that occur in living matter into three groups. Each of these groups was identified according to new terms that the pair had developed that were based on the degree to which specific information contained in an organism was reflected in different molecules. These three categories were:

1.Semantophoretic Molecules (or Semantides), which carry genetic information or a transcript of it. DNA, for example, was considered to be composed of primary semantides.

2. Episemantic Molecules, which are synthesized under control of tertiary semantides. All molecules built by enzymes were considered episemantic.

3. Asemantic Molecules, which are not produced by the organism and do not express (directly or indirectly) any of the information that the organism contains. In their discussion, Zuckerkandl and Pauling were quick to point out that certain asemantic molecules may shift form. Viruses, for example, can change form when integrated into the genome of the host; so too can vitamins when used and modified anabolically.

Semantides were considered most relevant to evolutionary history, but the term never caught on in biology, paleontology, or other allied fields relevant to the study of evolution. Nonetheless, whatever the nomenclature, the “semantides” that Zuckerkandl and Pauling wanted to investigate – DNA, RNA, and polypeptides – proved indeed to be precisely the treasure trove of information on evolutionary history that the duo had hoped would be the case.


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A figure from the French translation of Zuckerkandl and Pauling’s 1964 paper.

Fundamentally, Zuckerkandl and Pauling aimed to elucidate how one might gain information about the evolutionary history of organisms through comparison of homologous polypeptide chains. In examining these substances, the researchers sought specifically to uncover the approximate point in time at which the last common ancestor between two species disappeared. In essence, it is this approach that we speak of when we use the terms “molecular clock” or “evolutionary clock.”

Zuckerkandl and Pauling argued that, by assessing the overall differences between homologous polypeptide chains and comparing individual amino acid residues at homologous molecular sites, biologists and paleontologists would be better equipped to evaluate the minimum number of mutational events that separated two chains.

With this information in hand, researchers would thus be empowered to exhume the details of evolutionary history between species, as inscribed in the base sequences of nucleic acids. This set of data, they believed, would hold even more useful information than would corresponding polypeptide chain amino acid sequences, since not all substitutions in the nucleotides would be expressed by differences in amino acid sequence.


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A table from Zuckerkandl and Pauling’s 1965 Bruges paper.

As their work moved forward, Pauling and Zuckerkandl published another paper, 1965’s “Evolutionary Divergence and Convergence in Proteins.” This publication appeared in Evolving Genes and Proteins, a volume that emerged from a conference that the two had attended in Bruges, Belgium.

By this point, the duo’s idea of the molecular clock, or “chemical paleogenetics,” had elicited opposition from organismal evolutionists and taxonomists, as well as some biochemists. Now referring to their “semantides” simply as informational macromolecules, Zuckerkandl and Pauling used the 1965 meeting to argue strongly against their skeptics. Zuckerkandl chided

Certainly we cannot subscribe to the statement made at this meeting by a renowned biochemist that comparative structural studies of polypeptides can teach us nothing about evolution that we don’t already know.

Pauling likewise added that

Taxonomy tends, ideally, not toward just any type of convenient classification of living forms (in spite of a statement to the contrary made at this meeting).

Directly challenging those present who were attempting to discredit the idea of the molecular clock, the pair insisted that taxonomy tended toward a phyletic classification based on evolutionary history. Since the comparison of the structure of homologous informational macromolecules allowed for the establishment of phylogenetic relationships, the Zuckerkandl-Pauling studies of chemical paleogenetics therefore had earned a place within the study of taxonomy. This, they argued, was true both as a method of reinforcing existing phyletic classifications and also of increasing their accuracy. Specifically, the two claimed that

The evaluation of the amount of differences between two organisms as derived from sequences in structural genes or in their polypeptide translation is likely to lead to quantities different from those obtained on the basis of observations made at any other higher level of biological integration. On the one hand, some differences in the structural genes will not be reflected elsewhere in the organism, and on the other hand some difference noted by the organismal biologist may not be reflected in structural genes.

Indeed, it was these early observations, coupled with additional work conducted by those scientists who took their ideas seriously, that allowed for the development of a successful measure of rates of evolutionary change over time. Without these data, modern paleontologists, physical anthropologists, and geneticists would not be able to accurately determine evolutionary histories. Today, this technique has been systematized and specialized in the field of bioinformatics, which is now foundational to many studies in both biology and medicine.

The taxonomic purpose of the molecular clock, however, was only a byproduct of Zuckerkandl and Pauling’s main ambitions in studying paleogenetics: to better understand the modes of macromolecular transformations retained by evolution; to elucidate the types of changes discernible in information content; and – most importantly for Pauling – to identify the consequences of these changes for a given organism.


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Linus Pauling, 1992.

Despite its considerable potential, the work of Zuckerkandl and Pauling, though conducted at such a critical juncture in a nascent field, was largely forgotten as recently as the early 1990s. In fact, in Allan Wilson and Rebecca Cann’s 1992 article, “The Recent African Genesis of Humans,” it was implied that the concept of the molecular or evolutionary clock was first developed and employed by a Berkeley anthropologist, Vincent Sarich. Sarich had collaborated with Wilson in 1967 to estimate the divergence between humans and apes as occurring between four to five millions years ago.

Pauling was still alive in 1992, and seeing this article he duly wrote to the editor of its publisher, Scientific American, pointing out that that, in fact, he and Zuckerkandl had, in 1962, issued their own estimate of the disappearance of the last common ancestor of gorilla and man. Zuckerkandl and Pauling’s calculations had yielded a divergence at about 7.6 million years before present, which Pauling pointed out was much closer than Sarich’s figure to the more recent estimates of divergence determined by Sibley and Ahlquist in 1984 and 1987. Notably, Pauling and Zuckerkandl’s estimate continues to remain closer to more contemporary notions of 8 to 10 million years.

Today, Emile Zuckerkandl and Linus Pauling are remembered as having first championed the notion of the molecular clock, even if many of the details now deemed as fundamental still needed to be ironed out by an array of scientists who followed. Regardless, as in so many other areas of science, Pauling proved once more to be on the ground floor of a new discipline. This was an academic venture that continued also to serve the younger Zuckerkandl well, as he continued on through a prolific career in science that concluded with his passing in 2013.

Molecules as Documents of Evolutionary History

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Linus Pauling and Emile Zuckerkandl, 1986.

[Part 1 of 2]

“Of all natural systems, living matter is the one which, in the face of great transformations, preserves inscribed in its organization the largest amount of its own past history. We may ask the question: Where in the now living systems has the greatest amount of their past history survived, and how it can be extracted?”

-Linus Pauling and Emile Zuckerkandl, 1964

Austria-born Emile Zuckerkandl fled to Paris with his parents to escape the Nazi occupation of his homeland when he was only sixteen. Twenty years Linus Pauling’s junior, this extraordinary scientific mind was nurtured through the study of the biological sciences at the University of Illinois in the United States, and the Paris-Sorbonne University in France. During the course of these studies, Zuckerkandl developed a particularly keen interest in the molecular aspects of physiology and biology, and is now regarded to have been a major contributor to both fields.

Zuckerkandl first met Linus Pauling in 1957, a time period during Pauling himself was spearheading the new study of molecular disease, following his earlier, groundbreaking discovery of the genetic basis of sickle cell anemia. Two years later, Zuckerkandl joined Pauling as a post-doc in the Chemistry and Chemical Engineering Division at the California Institute of Technology. Once arrived, Zuckerkandl was encouraged by Pauling to study the evolution of hemoglobin, a research project that was informed by a basic and crucial assumption that the rate of mutational change in the genome is effectively constant over time.

This assumption was something of a hard sell for biologists at the time, due to the prevailing belief within the discipline that mutations were effectively random. Undaunted, Pauling and Zuckerkandl moved forward with their project and ultimately created a model that, over time, ushered in major changes to the conventional wisdom.


The Pauling-Zuckerkandl project was first revealed to the world in a co-authored paper that appeared in 1962’s Horizons in Biochemistry, a volume of works written and dedicated to the Nobel winning physiologist Albert Szent-Györgyi. The paper, titled “Molecular Disease, Evolution, and Genic Heterogeneity,” is regarded today as a foundational work in its application of molecular and genetic techniques to the study of evolution.

At the time that Pauling and Zuckerkandl wrote this first joint paper, Pauling was, as the title of the work might suggest, very interested in molecular disease; so much so that he was thinking about molecular disease and evolution as occupying two sides of the same coin. Defining life as “a relationship between molecules, not a property of any one molecule,” Pauling believed that disease, insofar as it was molecular in basis, could be defined in exactly the same way. Since both evolution and molecular disease were merely expressions of relationships between molecules, the distinction between the two became blurred for Pauling, who felt that the mechanism of molecular disease represented one element of the mechanism of evolution.

In their paper, Pauling and Zuckerkandl outlined their point of view as follows:

Subjectively, to evolve must most often have amounted to suffering from a disease. And these diseases were of course molecular. …[T]he notion of molecular disease relates exclusively to the inheritance of altered protein and nucleic acid molecules. An abnormal protein causing molecular disease has abnormal enzymatic or other physicochemical properties. Changes in such properties are necessarily linked to changes in structure. The study of molecular diseases leads back to the study of mutations, most of which are known to be detrimental. A bacterium that loses by mutation the ability to synthesize a given enzyme has a molecular disease. The first heterotrophic organisms suffered from a molecular disease, of which they cured themselves by feeding on their fellow creatures. At the limit, life itself is a molecular disease, which it overcomes temporarily by depending on its environment.

These assertions – in particular that “life itself” was a molecular disease – were so strange and seemingly outrageous that many biologists dismissed the paper outright. However, the basic idea that the pair was considering simultaneously sparked the interest of many other scientists who willing to entertain the consequences of this mode of thinking. If Pauling and Zuckerkandl were right, then every vitamin required by human beings stood as a witness bearing testimony to the molecular diseases that our ancestors contracted hundreds of millions of years ago. These “diseases” would manifest negative symptoms only when the curative properties of the nutrients gained from our natural environment through food and drink proved insufficient to dampen their effects.


This line of reasoning provided the impetus for Pauling and Zuckerkandl to begin examining differences between the genetic code as a tool to better understand evolutionary history. Though they did not call it “the molecular clock” at the time, the concept served as the foundation for the genetic analysis of species over long periods of evolutionary history.

Fundamental to Pauling and Zuckerkandl’s argument was the notion that there was no reason to place molecules at specific points “higher” or “lower” on an evolutionary scale. Horse hemoglobin, for example, is not less organized or complex than is human hemoglobin, it is simply different. The same is true for the genetic information contained in the hemoglobin of humans as compared to other primates, such as gorillas.

As Zuckerkandl examined differences of these sorts, he was not surprised to find that the peptide sequences of a gorilla were more similar to a human’s than a horse’s were to either. He and Pauling then began to consider how these sequences must be indicative of the millions of years of separate evolution that had passed since the disappearance of the last common ancestor linking horses and primates.

While compelling in its own right, for Pauling the chief purpose of understanding these differences was to discern crucial information about the human condition and to define the parameters of optimal health. Indeed, Pauling fundamentally believed that an improved understanding of the transitions that the genetic code had undergone would ultimately reveal new and effective treatments for molecular diseases.


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Table I from Pauling and Zukerkandl’s 1962 paper.

To demonstrate the efficacy of their methodology, Pauling and Zuckerkandl calculated the number of genetic differences that exist between the alpha and beta chains of hemoglobin peptide sequences in horses, humans, and gorillas, which they then used to determine the time that had elapsed since the erasure of the last common ancestor linking these species. In seeming support of their claims, the authors found that their figures matched pretty closely with data uncovered by paleontologists.

Despite this, the impact of Pauling and Zuckerkandl’s paper dissipated pretty quickly. For other established figures in the field, Pauling and Zukerkandl had failed to prove the essential assumption that evolution should proceed with relative uniformity over time. Lacking a clear reason to accept that genetic change occurs at a constant rate, there was no compelling reason to believe that Pauling and Zuckerkandl’s molecular clock should give an accurate picture of evolutionary history.

Nonetheless, the idea of the molecular clock found a degree of traction among biologists who valued its potential to corroborate and increase the accuracy of existing phylogenetic assignments. And as we’ll discuss in our next post, Pauling and Zuckerkandl continued to explore their ideas, eventually building a body of work that came into far greater favor a few decades later.

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.

The Iron-Oxygen Bond in Oxyhemoglobin

Pastel drawing of the hemoglobin molecule by Roger Hayward, 1964.

Part of the beauty of studying the life and work of Linus Pauling is that doing so often affords the opportunity to look at how the science of today has developed from questions that were once unanswered and widely debated. One such question was how hemoglobin, the protein in red blood cells, binds to and releases oxygen as it is inhaled and carried to the body’s tissues.

In 1959, Max Perutz used x-ray crystallography to obtain an image of oxyhemoglobin, a hemoglobin protein bound to an oxygen molecule. This was a major breakthrough in many ways. For one, it allowed chemists to observe an image of a three-dimensional protein found in humans for the first time. The imagery also provided tantalizing hints about the specific chemistry that might explain oxyhemoglobin’s structure.

Unfortunately, creating an image of the molecular structure didn’t solve everything, as Perutz himself would reflect in a 1978 article, “Hemoglobin Structure and Respiratory Transport.”

We were like explorers who have discovered a new continent, but it was not the end of the voyage, because our much-admired model did not reveal [hemoglobin’s] inner workings.


The Joseph Weiss Medal, which commemorates his work as a radiation chemist.

The Joseph Weiss Medal, which commemorates his work as a radiation chemist.

Perutz’s work naturally incited biochemists to further explore the structure of hemoglobin. While it was known that the oxygen-carrying heme group in hemoglobin is composed of nitrogen, carbon, and an oxygen-binding iron, there was much debate over what kind of bond could cause the union and dissociation of these elements.

In 1964, Joseph Weiss, a professor at Newcastle University in England, attempted to answer the question of what specific bond forms between iron and oxygen. Weiss’s conclusions were published in a 1964 article, “Nature of the Iron–Oxygen Bond in Oxyhæmoglobin”.

According to Weiss, the iron in hemoglobin would need to be in the ferric state (iron with an ionic charge of +3) in order to account for hemoglobin’s behavior in oxygen transport.  He believed that ferric iron would also explain hemoglobin’s spectroscopy (the wavelengths of light reflected by a  molecule). Pauling, however, disagreed with Weiss.


Pauling, Max Delbruck and Max Perutz, 1976.

Interestingly, Pauling had been looking into the subject of the iron-oxygen bond in hemoglobin since 1948, when he presented a paper titled “The Electronic Structure of Hemoglobin” at a symposium in Cambridge, England. Pauling’s presentation considered advances in x-ray diffraction and quantum mechanics to propose a structure for the heme group in the protein. Unlike Weiss, Pauling believed that the iron-oxygen bond in oxyhemoglobin would require ferrous iron (an iron with an ionic charge of +2) to form a double bond (a bond involving two electrons) with oxygen as it was being transported throughout the body.  Weiss’s paper did little to change Pauling’s mind on the subject.

In 1964, Pauling wrote “Nature of the Iron–Oxygen Bond in Oxyhæmoglobin,” a direct response to Weiss’s article with the same title. In it, Pauling stated

I conclude that oxyhæmoglobin and related hæmoglobin compounds are properly described as  containing ferrous iron, rather than ferric iron, that their electronic structure involves essentially the formation of  a double bond between the iron atom and the near-by oxygen atom in  oxyhæmoglobin

Pauling’s interest in the components of blood had emerged early on in his career. In 1948 he suggested using hemoglobin to test his earlier ideas about bonds that had remained unexplored, as the structure of the protein had been hitherto not fully understood. This was a pursuit that he in which he strongly believed: in his Cambridge talk, “The Electronic Structure of Hemoglobin,” he had concluded that

even the great amount of work that would be needed for a complete determination of [hemoglobin’s] structure, involving the location of each of the thousands of atoms in its molecule, would be justified.

Many years later, in his 1992 article “The Significance of the Hydrogen Bond,” Max Perutz stated that that Pauling’s words, as published in 1949, were among the inspirations propelling his own work a decade later.


“The Electronic Structure of Hemoglobin” wasn’t the only publication by Pauling that inspired Perutz. In 1970, he used Pauling’s “The Magnetic Properties and Structure of Hemoglobin” to further his own study of the structure of hemoglobin, work which finally led to the discovery that the iron-oxygen binding in hemoglobin depends on the electronic spin transition of the iron atom.

Essentially, Perutz found that when the ferrous iron in hemoglobin is in a low spin state, its higher d-orbitals are unoccupied by electrons, which allows oxygen to form a bond with iron. In a high spin state, the electrons in ferrous iron are occupying all d-orbitals in the atom and oxygen remains unbound.

This suggests that the more likely structure for hemoglobin involves a single bond between iron and the oxygen molecule, not the double bond that Pauling had proposed in 1948 and again in 1964.  But Pauling was correct with respect to the presence of ferrous iron in the compound, and he had been able to make this determination before any crystallographic pictures were available to him.

 

Pauling and Perutz: The Later Years

[Concluding our series on Max Perutz, in commemoration of the Perutz centenary.]

In 1957, Max Perutz and Linus Pauling wrote to each other again on a topic that was new to their correspondence. This time Pauling asked Perutz to sign his petition to stop nuclear weapons tests, a request to which Perutz agreed.

Signature of Max Perutz added to the United Nations Bomb Test Petition, 1957.

Signature of Max Perutz added to the United Nations Bomb Test Petition, 1957.

As the decade moved forward, the discovery of the double helical structure of DNA attracted ever more attention to the work of James Watson and Francis Crick. In May 1958, Perutz asked Pauling to sign a certificate nominating his colleagues Crick and John Kendrew to the Royal Society. Pauling agreed, though stipulated that Kendrew’s name be placed first on the nomination, as he expected that Crick would get more support. As with Pauling’s bomb test petition a year earlier, Perutz agreed.

At the beginning of 1960, William Lawrence Bragg wrote to Pauling about nominating Perutz, along with Kendrew, for the 1961 Nobel Prize in Physics. Pauling was hesitant about the nomination, thinking it was still early, as their work on hemoglobin structure had only recently been published. Pauling also felt that Dorothy Hodgkin should be included for her work in protein crystallography. Bragg thought this a good idea and included Hodgkin in his nomination.

By March, Bragg’s nominations had gone through and Pauling was asked to supply his opinion. After spending some time thinking about the matter, Pauling wrote to the Nobel Committee that he thought that Robert B. Corey, who worked in Pauling’s lab, should be nominated along with Perutz and Kendrew for the Nobel Prize in Chemistry instead. Pauling felt that if Perutz and Kendrew were included in the award, Corey should be awarded half, with the other half being split between Perutz and Kendrew. Pauling also sent a letter to the Nobel Committee for Physics, indicating that he thought that Hodgkin, Perutz, and Kendrew should be nominated for the chemistry prize. Pauling sent a copy of this letter to Bragg as well.

Pauling’s letter to the Nobel Committee, March 15, 1960. pg. 1.

Pg. 2

In July, Bragg replied to Pauling that he was in a “quandary” about Corey, as he was “convinced that” Corey’s work “does not rank in the same category with that which Mrs. Hodgkin or Perutz and Kendrew have done.” Perutz and Kendrew’s efforts, he explained, had theoretical implications directly supporting Pauling’s own work, whereas Corey’s research was not that “different from other careful analyses of organic compounds.” Once everything was sorted out, Perutz and Kendrew were awarded the Nobel Prize for Chemistry in 1962 (the same year that Watson and Crick, along with Maurice Wilkins, won in Physiology/Medicine, and Pauling, though belated for a year, won the Nobel Peace Prize) and Hodgkin received the Nobel Prize for Chemistry in 1964. Robert Corey never was awarded a Nobel Prize.


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

Perutz and Pauling corresponded very little during the 1960s, with Perutz writing only to ask for Pauling’s signature, once for a photograph that would be displayed in his lab and a second time for a letter to Italian President Antonio Segri in support of scientists Domenico Marotta and Giordano Giacomello, who were under fire for suspected misuse of funds.

In 1971 Perutz read an interview with Pauling in the New Scientist which compelled him to engage Pauling on scientific questions once again. Perutz was surprised to have read that Pauling had tried to solve the structure of alpha keratin as early as 1937 and that his failure to do so led him to study amino acids. Perutz wrote that had he known this in 1950, he, Bragg and Kendrew might not have pursued their own inquiry into alpha keratin. Pauling responded that he thought his efforts had been well-known as he and Corey had made mention of them in several papers at the time. Pauling explained that he had difficulties with alpha keratin up until 1950, when he finally was able to show that the alpha helix best described its structure. Perutz replied that he was aware of Pauling and Corey’s work and the alpha helix, but was surprised that Pauling’s early failure to construct a model led him to a more systematic and fruitful line of research.

Perutz also wondered whether Pauling had seen his article in the previous New Scientist, which reflected on Pauling and Charles Coryell’s discovery of the effect of oxygenation on the magnetic qualities of hemoglobin. Perutz saw this as providing “the key to the understanding of the mechanism of haem-haem [heme-heme] interactions in haemoglobin.” Pauling responded that he had not seen Perutz’s article but would look for it, and also sent Perutz a 1951 paper on the topic. Perutz took it upon himself to send Pauling his own article from the New Scientist.

A few years later, in 1976, Perutz again headed to southern California to attend a celebration for Pauling’s 75th birthday, at which he nervously gave the after dinner speech to a gathering of 250 guests. Before going to the event in Santa Barbara, Perutz stopped in Riverside and visited the young university there, which impressed him. Perutz wrote to his family back in Cambridge that he wished that “Oxbridge college architects would come here to learn – but probably they wouldn’t notice the difference between their clumsy buildings and these graceful constructions.”

Perutz also visited the Paulings’ home outside Pasadena, which elicited more architectural comments. Perutz described to his family how the Pauling house was shaped like an amide group, “the wings being set at the exact angles of the chemical bonds that allowed him to predict the structure of the α-helix.” Perutz asked Pauling, perhaps tongue in cheek as he thought the design somewhat conceited, “why he missed the accompanying change in radius of the iron atom.” Pauling replied that he had not thought of it.

Bertrand Russell and Linus Pauling, London England. 1953.

In preparation for his speech, Perutz also took some time to read No More War! which he concluded was as relevant in 1976 as when it was first published in 1958. Perutz saw Pauling’s faith in human reason as reminiscent of Bertrand Russell’s. Indeed, the many similarities between the two were striking to Perutz, and he included many of them in his talk, “except for their common vanity which I discreetly omitted.” In a personal conversation, Perutz asked Pauling about his relationship with Russell which, as it turned out, was mostly concerned with their mutual actions against nuclear weapons. Perutz was somewhat disappointed that “they hardly touched upon the fundamental outlook which I believe they shared.”


Perutz and Pauling were again out of touch for several years until April 1987, when Pauling traveled to London to give a lecture at Imperial College as part of a centenary conference in honor of Erwin Schrödinger. Pauling’s contribution discussed his own work on antigen-antibody complexes during the 1930s and 1940s, during which he shared a drawing that he had made at the time. Perutz was in attendance and noticed how similar Pauling’s drawing was to then-recent models of the structure that had been borne out of contemporary x-ray crystallography. Perutz sent Pauling some slides so that he could judge the similarities for himself.

Flyer for Pauling's 90th birthday tribute, California Institute of Technology, February 28, 1991.

Flyer for Pauling’s 90th birthday tribute, California Institute of Technology, February 28, 1991.

The final time that Pauling and Perutz met in person was for Pauling’s ninetieth birthday celebration in 1991. Perutz, again, experienced stage fright as he gave his speech. But he was encouraged afterwards, especially after receiving a compliment from Francis Crick who, according to Perutz, was “not in the habit of paying compliments.” Perutz told his family that the nonagenarian Pauling “stole the show” by giving one speech at 9:00 AM on early work in crystallography and then another speech at 10:00 PM on his early years at Caltech. Perutz found it enviable that Pauling stood for both lectures and was still getting around very well, though he held on to the arm of those with whom he walked. Without coordinating, Perutz and Pauling also found a point of agreement in their talks, noting that current crystallographers were “so busy determining structures at the double” that they “have no time to think about them.” This rush often caused them to miss the most important aspects of the newly uncovered structures.

Just as Perutz first encountered Pauling through one of his books, The Nature of the Chemical Bond, so too would Pauling’s last encounter with Perutz be through a book, Perutz’s Is Science Necessary? Pauling received the volume in 1991 as a gift from his friends and colleagues Emile and Jane Zuckerkandl. Pauling’s limited marginalia reveal his interest in the text’s discussions of cancer and aging research. Aged 90 and facing his own cancer diagnosis, Pauling was particularly drawn to Perutz’s review of François Jacob’s The Possible and the Actual which sought, but did not find, a “death mechanism” in spawning salmon. Pauling likewise highlighted the book’s suggestion that “like other scientific fantasies…the Fountain of Youth probably does not belong to the world of the possible.” And Pauling made note of particular individuals that he had known well, like John D. Bernal and David Harker. Pauling deciphered the latter’s identity from Perutz’s less-than-favorable anonymous portrayal.

Pauling also noted spots where Perutz wrote about him. While most of these references were positive and focused on topics like Pauling’s influence on Watson and Crick and his breakthroughs on protein structure, one in particular was not. Perhaps less cryptic than the reference to Harker, Perutz described how “one great American chemist now believes that massive doses of vitamin C prolong the lives of cancer patients,” following it with “even more dangerous are physicians who believe in cancer cures.”

While critical, Perutz really meant the “great” in his comment and he continued to repeat it elsewhere. After Pauling passed away in August 1994, Perutz told his sister Lotte that “many feel that he [Pauling] was the greatest chemist of this century” while also being “instrumental in the protests that led to Kennedy and Macmillan’s conclusion of Atmospheric Test ban.”  He reiterated this idea in the paragraph that concluded his obituary of Pauling, published in the October 1994 issue of Structural Biology.

Pauling’s fundamental contributions to chemistry cover a tremendous range, and their influence on generations of young chemists was enormous.  In the years between 1930 and 1940 he helped to transform chemistry from a largely phenomenological subject to one based firmly on structure and quantum mechanical principles.  In later years the valence bond and resonance theories which formed the theoretical backbone of Paulings work were supplemented by R. S. Mullikens’ molecular orbital theory, which provided a deeper understanding of chemical bonding….Nevertheless resonance and hybridization have remained part of the everyday vocabulary of chemists and are still used, for example, to explain the planarity of the peptide bond.  Many of us regard Pauling as the greatest chemist of the century.

Pauling and Perutz in the Golden Age of Protein Research

Max Perutz, 1987. Image Credit: Graham Wood.

Max Perutz, 1987. Image Credit: Graham Wood.

[Part 3 of our series celebrating the Perutz centenary.]

In 1939 Max Perutz’s girlfriend gave him a book token for Christmas. Working on finishing his dissertation on the structure of hemoglobin, Perutz used that token to purchase Linus Pauling’s recently published text, The Nature of the Chemical Bond.

In the obituary of Pauling that he wrote some fifty-five years later, Perutz described how the “book transformed the chemical flatland of my earlier textbooks into a world of three-dimensional structures” and “fortified my belief, already inspired by J. D. Bernal, that knowledge of three-dimensional structure is all-important and that the functions of living cells will never be understood without knowing the structures of the large molecules composing them.”  The purchase of Pauling’s book marked the beginning of a long, fruitful and sometimes contentious correspondence between the two men, working on separate continents but united by similar interests.


Not until 1946 did Perutz first write to Pauling, asking for assistance as he labored through his research on the structure of hemoglobin. The Cavendish Laboratory, where Perutz was located, did not have the latest equipment that was available to Pauling at Caltech. In particular, Perutz needed a Hollerith punch-card machine to carry out calculations of the three-dimensional Patterson-Fourier synthesis. Perutz knew that Pauling’s lab was already conducting calculations of this sort and that the work Perutz was doing “would have to be done sooner or later, if the molecular structure of the proteins is to be worked out.”

As such, Perutz hoped that someone in Pauling’s lab might do the calculations for him. Pauling was not moved enough by Perutz’s request to offer the labor of his own team, replying that enlisting someone do such work in a “routine way” could lead to confusion. Pauling did offer that Perutz come to Pasadena, or send a surrogate to do the work, if he could find the money. Perutz was unable to support such an undertaking and so ended that conversation.

Linus Pauling and Lord Alexander R. Todd. Cambridge, England. 1948.

Two years later, in 1948, Pauling was in England, enjoying a stint as George Eastman Professor at Oxford. It was during this time that he and Perutz met for the first time in person. Perutz described his first experiences of Pauling’s lectures, in which

he would reel off the top of his head atomic radii, interatomic distances and bond energies with the gusto of an organist playing a Bach fugue; afterwards he would look around for applause, as I had seen Bertrand Russell do after quoting one of his eloquent metaphors.

The two also found time to talk together about their own particular research projects.

Pauling’s work at Oxford touched directly on Perutz’s own program, in what would become a oft-noted story in twentieth century history of science. As Pauling lay in bed with a cold, he did not stop working, choosing to spend his time making planar peptide models with paper chains. From his paper folding exercises, Pauling, according to Perutz’s obituary, “found a satisfactory structure by folding them into a helix with 3.6 residues per turn.” (A story that Pauling relayed many times himself.) The structure would come to be known as the alpha helix.

After Pauling recovered from his illness, Perutz showed him his own model of a polypeptide chain which was part of his larger hemoglobin model and was similar to fibers described by William Astbury. To Perutz’s “disappointment, Pauling made no comment,” and gave no hint as to his own breakthrough, which he announced the next year in a “dramatic lecture.”  That later unveiling of the alpha helix gave rise to a famous Perutz anecdote, which later informed the title of a book of essays that Perutz published.

When I saw the alpha-helix and saw what a beautiful, elegant structure it was, I was thunderstruck and was furious with myself for not having built this, but on the other hand, I wondered, was it really right?

So I cycled home for lunch and was so preoccupied with the turmoil in my mind that I didn’t respond to anything. Then I had an idea, so I cycled back to the lab. I realized that I had a horse hair in a drawer. I set it up on the X-ray camera and gave it a two hour exposure, then took the film to the dark room with my heart in my mouth, wondering what it showed, and when I developed it, there was the 1.5 angstrom reflection which I had predicted and which excluded all structures other than the alpha-helix.

So on Monday morning I stormed into my professor’s office, into [William Lawrence] Bragg’s office and showed him this, and Bragg said, ‘Whatever made you think of that?’ And I said, ‘Because I was so furious with myself for having missed that beautiful structure.’ To which Bragg replied coldly, ‘I wish I had made you angry earlier.’

 


Once Pauling returned to Pasadena, he and Perutz fell into a minor quarrel. In December 1950, Perutz had heard that Pauling had been “annoyed” by Perutz and John Murdoch Mitchison’s paper, “State of Hæmoglobin in Sickle-Cell Anæmia,” which had been published in Nature that October. Pauling was upset that Perutz and Mitchison had suggested that crystallization caused cells to sickle without properly citing his own seminal work on the subject.

In a December letter, Perutz said he was “very disappointed” that Pauling was upset with the publication, not only because there was a reference to Pauling, et al. in its introductory paragraph, but “particularly because all the new experimental evidence we report seemed to fit in so beautifully with the basic ideas set out in” Pauling’s co-authored Science article, “Sickle Cell Anemia, a Molecular Disease,” published in November 1949. Perutz explained his position in more detail, noting,

There is perhaps a slight difference between our points of view. Whereas you regard the sickling as being due to an aggregation and partial alignment of hæmoglobin molecules by a lock and key mechanism, an interlocking of specific groups in neighbouring molecules, we regard the cause of the sickling as being simply a crystallization, due to abnormally low solubility of the reduced hæmoglobin. No specific interaction of the kind you mention need be involved in the second process, though it obviously may be…I am sorry that this misunderstanding between us should have arisen, particularly as I have spent much effort trying to convert unbelievers to your scheme.

Pauling waited until the following February to respond and explained his feeling that readers of Perutz’s article might conclude that Perutz was making an original proposal. Having made this statement, Pauling, in his own way, moved beyond the quarrel by telling Perutz about his more recent work showing that “hemoglobin is not crystallized in the sickle cells, but is only converted to the nematic [or liquid crystal] state.” The ice broken, Perutz quickly responded by inviting Pauling to take part in informal discussions about protein structure at the Cavendish Laboratory before an annual conference, to be held in Stockholm. Pauling, however, could not attend.

The next year, Pauling attempted to visit England, this time to speak at a conference about the alpha helix, but was delayed due to his passport renewal being denied on account of his political activities. Perutz wrote that Pauling’s “absence had a sadly damping effect on our meeting at the Royal Society, and it made the discussion rather one sided as there was no none to answer the various objections to the α-helix raised by the Astburites and Courtlauld people” since Pauling’s supporters were unprepared to defend Pauling’s position without him. Perutz was also keen to show Pauling his own progress, an eagerness that Pauling reciprocated. By July Pauling had cleared up his passport problems and was able to spend time in person discussing his and Perutz’s work.


By 1953 Perutz and Pauling were quarrelling again over proper citation, though this time it was Perutz suggesting that Pauling had not given Francis Crick enough credit regarding the coiling of alpha helixes. Pauling explained to Perutz that, while he was at Cambridge the previous summer, he had talked with Crick and John Kendrew at length. During that conversation, according to Pauling,

There was only brief discussion of α keratin at this time, and, if my memory is correct, only a few sentences were said about the coiled coil, as Crick calls it. We discussed the fact that the 5.15-Å meridional reflection offers some difficulties of explanations, and that also there seemed to be a discrepancy in the density of α keratin. The discussion was very brief. Then Mr. Crick asked me if I had ever thought of the possibility that the α helixes were twisted about one another. I answered that I had. So far as I can remember, nothing more was said on this point.

Pauling went on to emphasize that “the idea was not a new one to me then” and that his own description of it in Nature was different from Crick’s understanding. Perutz ceded this point, adding that Pauling’s differences with Crick “stimulated Crick to clarify his own” ideas on the coiling of alpha helixes. More generally, Perutz found that the competition that arose between the two labs as they worked on similar problems helped to push each forward, thus leading to positive advances.

The famous group photo of the Pasadena Conference on the Structure of Proteins, September 1953. Pauling stands front row, third from left. Perutz stands two rows behind Pauling. [Image credit: The Archives, California Institute of Technology]

That September, Perutz made his first visit to California in order to deliver a paper at the Pasadena Conference on the Structure of Proteins, at which were gathered all of the world’s major figures in the field, including Jim Watson and Francis Crick, newly famous for their double helical structure of DNA. Perutz told his wife, Gisela, that his paper was “well received.” Additionally, with all of the different perspectives presented, there was “an atmosphere of soberness, and a realization that no-one’s solution of the protein problem was complete, and every approach was still fraught with complications.” Perutz was also quite taken with the Paulings’ home and their hospitality, pointing out that Ava Helen had invited him “after one of the meetings for a swim in their garden.”

Correspondence between Perutz and Pauling dipped a bit after the conference, though Pauling did take a moment to congratulate Perutz on being elected to the Royal Society the following Spring. While the exchange was brief, it reflected the long relationship built up between the two over the preceding years and, in particular, a confluence of work that had boosted the esteem of both scientists.

Perutz had begun looking at the structure of wool proteins back in 1951, thinking that there might be similarities to hemoglobin. He became excited after finding Pauling’s work on alpha helixes in fibers, thinking that the structure might be present in wool as well. His initial studies resulted in disappointment, but after adjusting the angle at which he was taking his x-rays by 30 degrees, he compiled new data that confirmed Pauling’s alpha helix structure. After applying it to his own work on hemoglobin, Perutz told Pauling “the discovery of this reflexion in haemoglobin has been the most thrilling discovery of my life…there is no doubt that it is a universal feature at least of all fibers of the α type. Whether all crystalline proteins show it remains to be seen.” Not suprisingly, Pauling was also “very pleased” with this discovery.

This research opened the door for Perutz to be considered by the Royal Society. But it was his development of a technique for determining a three-dimensional view of structures derived from x-ray crystallography that assured his election. He did this be attaching mercury atoms to hemoglobin, which allowed him to figure out where the crest and trough of a given x-ray was in relation to the structure that appeared on the photos. Perutz later said that after he finished the work and published it in Nature at the end of 1959, he went skiing in the Alps, and by the time he returned he was famous, assuring his fellowship in the Royal Society.

Perutz’s Hemoglobin Breakthroughs and Later Work

Perutz with his hemoglobin molecule, 1959. Image credit: Life Sciences Foundation.

Perutz with his hemoglobin molecule, 1959. Image credit: Life Sciences Foundation.

[Part II of our survey of the life of Max Perutz, this time focusing on the years 1941-2002. Published in commemoration of the Perutz centenary, May 2014.]

Knowing that his parents were safe from Nazi persecution and able to return to the United States, circumstances began improving for Max Perutz. The Rockefeller Foundation reactivated his grant, allowing him to support himself while stateside as well as his parents in Cambridge, England. Perutz’s father was also able to find work as a laser operator during the war and afterwards qualified for a pension.

In September 1941, Perutz met Gisela Peiser, who was an accountant at the Society for the Protection of Science and Learning, an organization that assisted Jewish and other academic refugees fleeing from the Nazis. After a quick courtship, they were married the following March and, in December 1944, welcomed their daughter Vivien into the world. That same year, Perutz also found himself back in good stead with the British government and recruited to research ice strength for potential ice stations in the North Atlantic. The research did not work out, so Perutz returned to his work on hemoglobin at Cambridge. The next few years were spent trying to put together a secure source of income for him and his growing family. In the interim, he took out more loans and found a temporary fellowship.

Meanwhile, Perutz’s health continued to suffer. As his chronic gastrointestinal attacks became more unbearable, interfering with his daily activities more and more, Perutz began to seek out help. Most doctors he saw told him it was a psychological problem, but eventually one doctor recognized that the symptoms could be treated by a mixture of atropine and codeine. The remedy helped enough for Perutz to live more or less undisturbed by the problem for several years, though eventually that would change.


Perutz and John Kendrew, 1962. Image credit: Nobel Foundation.

Perutz and John Kendrew, 1962. Image credit: Nobel Foundation.

In 1947, the war now completed, Perutz, along with John Kendrew, was appointed to head the new Research Unit for the Study of the Molecular Structure of Biological Systems (Perutz later shortened the unit’s name to Molecular Biology Research) at the recently established Medical Research Council. Situated at the Cavendish Laboratory in the physics department, the group expanded on Perutz’s earlier application of x-ray crystallography to biological materials. Perutz, in this new administrative role, described his lab management as one where he would “leave people free to do what they wanted…if they were good scientists.”

One of the several student researchers that came through the lab was Francis Crick, who started work in 1949. Perutz had Crick look at the validity of his hemoglobin model, which was the culmination of roughly six years of research. Crick applied his mathematical training to show that the model was “nonsense.” Perutz accepted Crick’s assessment and later reflected that only in England at that time could a student be so critical of their principal investigator. Crick was eventually drawn away from hemoglobin research by James Watson, who came to the lab in 1951 to work under Kendrew on molecular structure, but his impact on the development of Perutz’s hemoglobin structure was long-lived.

Throughout the late 1940s, Perutz also continued his work on glaciers in the Alps and helped found the Glacier Physics Committee in 1947. Though he had trouble recruiting able assistants who could also ski (the first two broke their legs), the work gave Perutz and his family the opportunity to spend summers in the mountains. Perutz’s research led him to conclude that glaciers flowed faster at the surface than at the bottom.

Perutz’s digestive attacks began increasing in intensity in the early 1950s to the point where, in 1954, he was hospitalized for ten days. While there, doctors looked for possible causes but came up empty and could only prescribe bismuth, with little effect. What did help, for reasons Perutz did not understand, was visiting the Alps, and so he arranged for a trip after being released from the hospital. Unfortunately the attacks resumed as soon as he returned to Cambridge, pushing Perutz to his limits – he considered resignation and even contemplated suicide. In desperate straits, he arranged for another trip to the Alps that spring but, once there, continued to get worse and, as an added complication, came down with scurvy.

When he returned, Perutz sought out other doctors who might be able to help, eventually visiting Werner Jacobson, who was also at Cambridge. Jacobson thought Perutz’s symptoms sounded like those of Celiac disease. He suggested that his patient stop eating wheat, or more specifically gluten, which immediately improved Perutz’s condition. Whenever the symptoms appeared again, as they did in the early 1960s, Perutz could trace them back to gluten; he eventually stopped eating any form of bread, since even gluten-free flour contained small amounts of gluten that negatively affected his health.


Perutz in lecture. Image credit: Nature.

Perutz in lecture. Image credit: Nature.

Perutz’s improved physical condition coincided with the final years of his triumphant work on a determination of the structure of hemoglobin. After working out a solution to interpret x-ray diffraction photos of proteins three-dimensionally, Perutz came upon the structure in September 1959, submitting his findings to Nature before heading to the Alps to ski over the winter break. By the time he returned, he was famous.  It was quickly and widely acknowledged that his work comprised a major breakthrough for both chemistry and biology.  As Hugh E. Huxley wrote, in 2002

He was the first person to find out how to determine protein structure by X-ray crystallography, after many years of patient struggle, and he applied the technique to solve the structure of haemoglobin, the oxygen-carrying protein in blood….The results showed that it was possible to see, in the atomic detail necessary to understand mechanisms, the structure of the macromolecules that carry out many of the functions of a living cell. Such knowledge is basic to the revolution that has swept through biology in the past 50 years, and to modern medicine and biotechnology.

By Fall 1962 there were rumors that Perutz would be awarded the Nobel Prize for chemistry. As October arrived, he began receiving calls from the press, but did not quite trust them. As the calls continued, Perutz received a telegram and thought, along with the rest of the lab, that it may be from the Nobel committee. Alas, the message was only from Nature asking how many reprints of his article Perutz wanted. That afternoon however, Perutz received another telegram, the one he had been waiting for. The lab celebrated with a champagne party as Perutz and Kendrew had been awarded the Nobel Prize for Chemistry, and Watson and Crick, along with Maurice Wilkins, would receive the Nobel Prize in Physiology and Medicine.

Perutz continued to work on the hemoglobin structure after his rise to fame, next turning to the question of how the structure changed with the uptake of oxygen. His Nobel lecture described this continued research on the four subunits within hemoglobin that changed their structure as oxygen was taken up; the first description of how proteins changed in structure.

In the years that followed, Perutz focused more on why this change occurred. Aided by automated x-ray diffraction machines and able assistants, Perutz’s lab was able to turn out more measurements than ever before. But the measurements, as Perutz later related, did not make any sense. After one of his research assistants completed his postdoc, Perutz looked closer at his results and realized that the new x-ray instruments had not been calibrated correctly.

In 1967, with all the bugs fixed, Perutz and his team put together the first atomic model of hemoglobin, but Perutz’s questions about why the structure changed still were not answered. By 1970, the lab was able to construct an oxygen-free model, allowing Perutz to compare it with the oxygenated model. As Perutz later described “there came this dramatic moment when between them, the models revealed the whole mechanism.” What he was able to see was how a slight movement of the iron atom triggered a change in the whole molecule. Thus, Perutz felt he was able to explain “all the physiological functions of hemoglobin on the basis of its structure.” The results were published in Nature.

Within the field, objections to Perutz’s explanation were numerous and he spent much of the next two decades refuting criticisms and refining his own explanation. At the same time, his celebrity also rose among scientists as he was increasingly invited to give lectures all over Europe and North America. By 1975 Perutz’s fame outside of scientific circles had grown such that Queen Elizabeth II invited him to visit with her at Buckingham Palace. Afterwards, Perutz expressed his regrets to the Queen’s secretary that “she had made me talk away like an excited little boy about my own doings and that I never asked her anything about hers.” Nonetheless, Perutz did hope that the Queen would enjoy his gift, the autobiography of Charlie Chaplin.


Max Perutz with his hemoglobin model. Image credit: BBC.

Max Perutz with his hemoglobin model. Image credit: BBC.

By 1980 Perutz had begun to reach out to broader audiences more intentionally. Shortly after retiring from the chair of the Laboratory of Molecular Biology, Perutz wrote a memoir of his time there. This, in turn, inspired him to compile an account of his experiences during World War II and submit it to the New Yorker. Penned in 1980 but not published until 1985, “Enemy Alien” helped bring Perutz greater levels of fame, as he received more letters after its publication than he did congratulations for his Nobel Prize.

An Italian pharmaceutical company also approached Perutz in 1980 to give a lecture on the social implications of molecular biology. According to a 2001 interview, Perutz told the company that “molecular biology has no social implications,” but that he could talk about “science as a whole.” This spurred him to take more of an interest in broader scientific questions, ultimately leading him to adopt controversial stances combatting criticism of the Green Revolution, DDT use and nuclear power, among other issues in the headlines. It also evolved into an interest in philosophy – Karl Popper’s Open Society and its Enemies proved particularly impactful. By 1989, Perutz expanded his popular lectures into a book of essays, Is Science Necessary? which included writings that he had also done for the New York Review of Books as well as “Enemy Alien.”

While continuing to write for the New York Review of Books up to the end of his life, Perutz also pursued new research on proteins and hemoglobin, taking a particular interest in neurodegenerative diseases like Parkinson’s and Alzheimer’s. In 2001, right before he passed away, Perutz was still at the lab seven to eight hours a day (including lunch and tea), preparing a publication for the Proceedings of the National Academy of Sciences on the common structure of insoluble protein deposits in neurodegenerative diseases. He passed away at the age of 87, unable to reconcile his initial structure with x-ray diffraction photos which showed contradicting features that Perutz concluded arose from three different structures. The results were published in 2002, after Perutz had died, in two separate articles.