David Pressman

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David Pressman, 1937

[Part 6 of 6 in our series exploring Linus Pauling’s work on the serological properties of simple substances, and the colleagues who assisted him in this work.]

After a meeting with Karl Landsteiner in 1936, Linus Pauling began serious investigations into the link between antibodies and antigens, compiling notes for what would eventually become his serological series, a collection of fifteen papers published during the 1940s. Landsteiner had specifically piqued Pauling’s curiosity on the question of the human body’s specificity mechanism – e.g., how could the body produce antibodies tailored to lock onto and fight specific antigens?

Pauling ultimately surmised that the answer lie in the shape of the molecules, and in the type and number of bonding sites. He described this as a “lock and key” mechanism, otherwise termed as molecular complementarity. Throughout this project, which made a significant impact on the modern study of immunology, Pauling enlisted the help of many undergraduate, graduate, and doctoral students, including a promising young scholar named David Pressman.


David Pressman was born in Detroit, Michigan in 1916. He attended Caltech as an undergraduate, studying under Pauling and completing his degree in 1937. He stayed in Pasadena for his doctorate, earning it in 1940. During this time, he became a part of Pauling’s quest to unravel the structure of proteins, and was particularly involved with the antibody and antigen work.

By this point, Pauling and his colleague Dan Campbell felt confident enough in what they had learned about antibody specificity to attempt creating artificial antibodies. Pauling was enthusiastic about the practical application that such an endeavor might promise for physicians. Warren Weaver, Pauling’s primary contact at the Rockefeller Foundation, which was funding the work, cautioned Pauling against becoming overconfident, but still granted him enough money to hire Pressman full-time. Thus began Pressman’s career in immunology.

At Pauling’s request, Pressman stayed on at Caltech as a post-doc, and during this time the two became friends. In 1943, after failing to prove that they could synthesize antibodies, Pauling’s research team changed their focus from understanding the structural components of antibodies and antigens, to looking for the binding mechanism that allowed antibodies to attach to specific antigens through Van der Waals bonds. One outcome of this was their development of the theory of complementarity, a “lock and key” model in which molecules fit together because of the high levels of specificity that they show for one another.

Pressman authored three papers with Pauling during this phase, including a very important one titled “The Nature of the Forces between Antigen and Antibody and of the Precipitation Reaction,” published in Physiological Reviews. In this paper, the researchers discussed the historical significance of immunology within the context of structural chemistry. Speaking of the tradition in which they worked, Pauling and his colleagues wrote that “two of the most important advances in the attack on the problem of the nature of immunological reactions were the discovery that the specific precipitate contains both antigen and antibody, and the discovery that antibodies, which give antisera their characteristic properties, are proteins.”  In this paper, they also theorized that the immune system depends on structural and chemical forces to function.


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Pressman (at right) in the lab, ca. early 1960s.

In 1947, Pressman decided to pursue an interest in cancer research and moved on to the Sloan Kettering Institute in New York City to investigate the use of radioactive tracers as they pertained to cancer treatment.  The West Coast was never far from his thoughts however, and he often wrote back to friends comparing the two regions and asking for information about life in Pasadena. Of his new arrangements he observed, “The mechanics of living take a much greater part of the time in New York, so that I do not have as much time to do as much as I would like to or could do in Pasadena.”

Pressman’s first few years at Sloan-Kettering were difficult, not only because of the nature of the research that he was conducting – a continuation of the research that he started with Pauling – but because he was frequently forced to move both his lab and his residence, a source of continuous disruption for himself and his family. Sloan Kettering had just been established in the early 1940s and wasn’t formally dedicated until the year after Pressman moved there. Though it eventually became one of the nation’s leading biomedical research institutions, Pressman’s early experiences there coincided with institutional growing pains.

Eventually, as the environment at Sloan-Kettering became more stable, Pressman settled in to his position and provided Pauling with regular updates on his progress. The two often traded manuscripts back and forth, and each solicited technical advice from one another on their specific endeavors, which gradually grew further afield as time moved forward. At Kettering, Pressman continued to study antibody specificity and explored the potential use of radioactive antibodies for tumor localization to develop immunotoxins. In 1954, he left New York City for the Roswell Park Institution in Buffalo, remaining there until his death.


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60th birthday greetings sent to Pauling by David and Reinie Pressman, February 1961.

Pauling and Pressman remained in frequent contact for many years, focusing their voluminous correspondence primarily on work that Pressman continued to do as an outgrowth of their time together in Pasadena.  In July 1961, Pressman wrote that he and a colleague, Oliver Roholt, had potentially made a breakthrough with regard to the sequencing of the polypeptide chain associated with the region of specific binding sites in antibodies. He sent his manuscript, “Isolation of Peptides from an Antibody Site,” to Pauling for review prior to submission to Proceedings of the National Academy of Science. Pauling felt that the manuscript had been put together too quickly and challenged Pressman to do better. He annotated the manuscript with numerous suggestions, most of which Pressman adopted. Less than a week later, Pressman sent the manuscript back to Pauling with the corrections and Pauling transmitted it in to PNAS, where it was received favorably.

The late 1960s were a period of great activity and advancement for Pressman. In 1965, he received the Schoellkopf Medal, a prestigious award granted by the Western New York section of the American Chemical Society. In 1967, he became assistant director at Roswell and, in 1968, he published a book, The Structural Basis of Antibody Specificity. By all outside indications, Pressman’s life was going well.


In 1977 however, tragedy struck when Jeff Pressman, David and Reinie Pressman’s son, committed suicide at the age of 33. Jeff was an up-and-coming professor of political science at MIT, where he was well-liked by faculty and students. Up until a few months before his death, Jeff had seemed happy, both with his career and his life at home. In a letter to Pauling, Pressman described Jeff’s descent into depression as sudden, severe, and uncharacteristic. He also documented the events leading up to his son’s suicide, conveying that he and his wife had become increasingly convinced that the responsibility for the tragedy lay at the feet of a rheumatologist to whom Jeff had been seeking assistance for back pain.

Believing Jeff’s back pain to be primarily muscular in cause, the rheumatologist had prescribed Indocin in January 1977. According to multiple sources that Pressman later consulted, Indocin was a mood-changer, so much so that other patients had reported sudden depressive symptoms and, in severe cases, committed suicide a few months after starting the medication. To complicate matters, the rheumatologist had increased Jeff’s dose to a level that few patients could tolerate well, and had done so more rapidly than was advisable. When Jeff began complaining of insomnia, the rheumatologist prescribed two additional medications, both of which had the potential to worsen his depression. Jeff finally stopped taking Indocin, but the effects lingered. Jeff’s wife, Katherine, reported that Jeff had felt increasingly hopeless about his depression, even though he continued to work at MIT up until his death.


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David Pressman’s former secretary, Cheryl Zuber, posing with a plaque mounted in Pressman’s honor at the Cancer Cell Center, Roswell Memorial Institute, 1981.

In the wake of Jeff Pressman’s death, his colleagues at MIT published a collection of political essays dedicated in his honor. The dedication specifically called out Jeff’s commitment to his students and his impact as a teacher. In it, his colleagues wrote, “He cared deeply about public affairs and immersed himself in them because he genuinely felt that government at its best could improve peoples’ lives.”

Nonetheless, the loss took its toll and, for David Pressman, the only source of solace that he could identify was a return to work. In 1978, his focus in the laboratory was on localizing radio-iodinated antitumor antibodies. He later wrote to Pauling about chronic shoulder pain that he was experiencing, as he was aware of Pauling’s vitamin research and was in search of an alternative to the shoulder replacement surgery that had been recommended by his physician. Pauling put forth an argument for a megadose of vitamins, but Pressman was eventually diagnosed with osteoarthritis. By the end of the year, he was slowing down, both in his work and in his correspondence.

Two years later, in June 1980, Pauling received the news that David Pressman had jumped from the roof of Roswell Park Memorial Institute. In a letter to Pauling informing him of her husband’s death, Reinie Pressman cast about for answers. She wrote at length about the health problems that he had been experiencing, including partial hearing loss, prostate trouble, and chronic problems associated with the osteoarthritis in his right shoulder. She also confided that “You were a significant part of Dave’s happier past.” Pauling replied in kind, stating

I was very fond of David. Also, I owe much to him, because of the vigor and effectiveness with which he tackled scientific problems during the eight years that he worked with me. Much of the success of our program in immunochemistry was due to his contribution.

Carol Ikeda and Miyoshi Ikawa

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Linus Pauling, 1942

[Ed Note: Parts 5 and 6 of our series detailing Linus Pauling’s work on the serological properties of simple substances both focus on the intriguing life stories of three individuals with whom Pauling worked on this program of research.]

Over the years, Linus Pauling forged close relationships with many of his graduate and doctoral students, offering guidance that, in numerous cases, changed the course of a student’s career. During World War II, he fought particularly hard for two of his research assistants, Miyoshi Ikawa and Carol Ikeda. In both cases, Pauling’s intervention prevented these colleagues from being forcibly interned. Instead, Ikawa and Ikeda each moved on to graduate studies and fruitful careers in science.


Miyoshi “Mike” Ikawa was born in California in 1919 to first generation immigrant parents. He pursued undergraduate studies at Caltech, where he was a member of the Chemistry Club and Tau Beta Pi, and competed on the Fleming House wrestling team. When he graduated in 1941, he was already working in Pauling’s lab, preparing compounds and helping with the first three serological papers. Pauling subsequently served as his graduate advisor.

Carol Ikeda came to Caltech from Texas in 1939, having started his education at Paris Junior College in Texas. He transferred to Caltech with the intent to study chemistry and become an organic chemist. At Caltech, he stood out among many other very bright students; Pauling described him as “one of the top men in the class.” Not one to give compliments lightly, Pauling recognized Ikeda’s potential not only from his performance in class, but also from his work in organic research labs on campus. Before Ikeda had even decided to continue onto graduate studies at Caltech, Pauling had recruited him for the serological project as an assistant in the Immunochemistry department. Indeed, it is especially noteworthy that Ikeda and Ikawa both are listed as co-authors for Pauling’s first three serological papers, given that the first two papers were published while Ikeda and Ikawa were still undergraduates.


Up until World War II, it appeared that Ikawa and Ikeda were each moving well down the path toward successful careers in immunology, organic chemistry, or biochemistry. This all changed when President Franklin Roosevelt issued Executive Order 9066 and declared Pasadena to be a military zone.

Even before the attack on Pearl Harbor, U.S. citizens of Japanese descent faced discrimination on the basis of race as well as suspicions that they would prove more loyal to Japan than to the United States even if they were second- or third-generation citizens. Acutely aware of the mounting tension faced by American-born Japanese, Pauling was determined to support students bearing this burden and to make sure that they could find positions at Caltech for which they were suitably qualified.

Pauling was likewise clear in his understanding that other universities did not share his point of view. In the recommendations that he wrote, he provided full disclosure and acknowledged potential discomforts regarding race, an issue that many administrators would have preferred be left unacknowledged. In one particular reply to a request for recommendations, Pauling wrote

…the two best men scholastically in our graduating class are American born Japanese, Ikawa, and Ikeda. Although one of them has, I think, a satisfactory personality for teaching work, I doubt that you would be interested in appointing him because of his racial handicap.

Some universities responded positively to recommendations of this sort; the University of Iowa, for one, confirmed that race wouldn’t be a problem at all. Rather, Pauling’s Iowa contact assured that the institution shared Pauling’s stance and was committed to considering the qualifications of their applicants regardless of race. The reply went on to state,

While we have not had any American-born Japanese on our teaching staff, I see no reason why they would not get along satisfactorily, if they have the necessary intelligence and ability.


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Miyoshi Ikawa, 1941

Ikawa and Ikeda had been working on the serological project for more than a year when Pasadena was declared a military zone. Cognizant of the need to help his assistants relocate to a safer area, Pauling had a relatively easy time finding Ikawa a position as a graduate student at the University of Wisconsin, where he worked under Karl Paul Link. This move ultimately changed the course of Ikawa’s career. Before receiving his doctorate, Ikawa, along with Link and Mark A. Stahmann, synthesized warfarin and obtained a patent for it to be used as a rat poison. By 1950, warfarin (now commonly referred to as Coumadin) was being used to treat blood-clotting disorders such as thrombosis, because it was a strong anticoagulant. It still serves this purpose today.

With the war over, Ikawa was free to return to the West Coast, where he conducted postdoctoral research at Caltech and UC-Berkeley, before moving on to the University of Texas. In the early 1960s, he settled down and became a professor at the University of New Hampshire, where he began focusing on marine biotoxins. In 1972, he and his colleagues established the Paralytic Shellfish Monitoring Program for the state of Maine, a course of action that followed the first evidence of a red tide in the southern Gulf of Maine. Ikawa taught at the University of New Hampshire for twenty years and then spent most of his later career advising technical panels and partaking in peer review committees for federal research grants. He passed away in 2006.


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Carol Ikeda, 1941

Pauling had a harder time finding a position for Ikeda. In February 1942, shortly after Roosevelt released his executive order, Pauling sent a letter to Robert Millikan – the chairman of the Caltech Executive Council – about Ikeda’s progress and position. In this, Pauling tried to make the case that, while his serological research wasn’t directly related to defense work, its results could be valuable for their medical application. He also pointed out that finding someone as competent as Ikeda to continue these studies would be nearly impossible.

As it turned out, this approach backfired for Pauling, because so many people were nervous about having American-born Japanese involved in any war effort. Consequently, Millikan asked Pauling to vouch for Ikeda’s loyalty in order to allow Ikeda to continue “to undertake, under special arrangement, research work which may involve defense matters.” Pauling vouched for Ikeda’s work, but hesitated to comment on his loyalty, because he felt that someone with a more personal working relationship with Ikeda could give a better answer. He also suggested that Ikeda could be transferred to a teaching position if the issue of loyalty could not be resolved to Millikan’s satisfaction.

As Millikan deliberated, Pauling began to feel that Caltech might not be the best environment for Ikeda, even if he was transferred to a teaching position. In short order, Pauling contacted Michael Heidelberger, a faculty member at Columbia University’s College of Physicians and Surgeons. In doing so, Pauling offered Heidelberger a quid pro quo of sorts, suggesting that Heidelberger accept Ikeda into his program at Columbia in exchange for Pauling hosting one of Heidelberger’s researchers in Pasadena. This plan broke down when the Columbia researcher that Pauling had in mind wrote back to say that he could not accept an appointment at Caltech and that he wished to stay on at Columbia instead.

The situation was not improved much by Heidelberger’s blasé attitude toward the internment camps. Recognizing that “wholly” patriotic people would be unjustly punished, Heidelberger remained unconvinced that there was much that he or Pauling could do to alleviate the issue, an opinion shared by many. As would later become the norm, Pauling stood out here as a lonely voice in the scientific community.

For Ikeda, things worked out at the last minute. In April 1942, just two weeks before Ikeda was assigned to report to a camp, Pauling managed to find him a graduate position at the University of Nebraska, where he completed his Ph.D. in 1945. In 1947, Ikeda accepted an offer of employment from DuPont in Delaware, and then later moved within the company to Philadelphia. In 1962, he received a patent for a resinous coating material that he developed while working for DuPont. He passed away in Phoenix, Arizona in 1996, having enjoyed a successful life and career.

A Lifelong Quest for Peace

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Pauling and Ikeda at Soka University in Los Angeles, 1987

[Part 2 of 2 in a series on Pauling’s interactions with Daisaku Ikeda.]

Linus Pauling’s 1987 meeting with Japanese peace activist Daisaku Ikeda, in which the two discussed their lives and philosophies in great detail, clearly made an impression on both men. Not long after, Ikeda’s assistant, Tomosaburo Hirano, wrote to Pauling again, thanking him for meeting with Ikeda and asking about the possibility of his composing a manuscript for publication in Japan.

Later in 1988, just about a year after their first meeting, Ikeda wrote to Pauling directly to express interest in co-authoring a dialogue in order to “provide some suggestion for the young generation who are to shoulder the responsibility in the 21st century, as well as serve the cause of peace and prosperity of humankind.” The dialogue would be published in an interview format, based on the transcript of their meeting in Los Angeles and supplemented by additional material. The first step toward completion was for Pauling to answer a series of seventy-three questions regarding his outlook on life. Pauling was interested in the project and promptly responded to the questionnaire.


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Pauling and Ikeda in dialogue, 1987

Many of the questions developed for the dialogue concerned the evolution of Pauling’s views on war and peace over the course of his life. Pauling began by explaining that, as he was only thirteen years old when World War I started, he had few thoughts about international relations at the time. He did recall the conclusion of the war in 1918, as he participated in a victory parade held in Corvallis, Oregon, where he marched alongside other cadets serving in the Oregon Agricultural College Army Reserve Officers Training Corps.

By the dawn of the Second World War, Pauling was well-established in Pasadena, working at the California Institute of Technology. During the war years he directed much of his energy toward projects sponsored by the explosives division of the National Defense Research Committee, where his research was used to support the killing and maiming of enemy soldiers, including the Japanese. Though he would spend much of his life working to limit the amounts of human suffering on Earth, Pauling commented that he felt satisfaction at the conclusion of the war, heartened that Hitler “and his associates” had been denied their goal of gaining control of the planet.

Nonetheless, despite Pauling’s scientific support for the war effort, it was also the case that when J. Robert Oppenheimer asked him to head the Manhattan Project chemistry department at Los Alamos, he refused. Likewise, after the war’s end, it was the emerging development of nuclear weapons and the ongoing threat of nuclear war that prompted Pauling’s peace activism. Over time, this point of view evolved into a desire to eliminate all war from Earth.


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In 1990, the agreement for the Japanese version of the Pauling-Ikeda dialogue, In Quest of the Century of Life, was finalized, and this version of the book was subsequently published. That same year, Pauling delivered a commemorative lecture at the second Soka University Pacific Basin Symposium, held at the Los Angeles campus of Soka Gakkai University.

Pauling used this talk to reflect on the genesis of his peace activism in some detail. Pauling recalled that, following the detonation of nuclear bombs over Hiroshima and Nagasaki in 1945, the public first became aware of the existence of nuclear weapons. In short order, businessmen’s clubs and other civic groups began to request that Pauling deliver after-dinner talks on the nature of these powerful new weapons. The talks were meant to be purely educational, according to Pauling, and focused mostly on the nature of atomic nuclei and nuclear energy.

Pauling soon discovered however, that as he gave more talks of this kind, he found himself ending them with a short commentary on war in general. In these, he expressed his hope that the existence of nuclear weapons would act as a deterrent to future conflicts, which would instead be handled by an international system of law. Albert Einstein had conveyed a similar sentiment as early as 1946.

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Pauling speaking at Soka University, August 24, 1990.

But with the passage of time, as nuclear stockpiles grew and the magnitude of the bombs being produced increased from 20 kilotons to 20 megatons – more than a thousand times more powerful than the weapons used in Japan – Pauling and many others began to call for global disarmament. While this directive was partially heeded the world’s governments, many large militaries began looking for ways to profit on their slow but steady draw down in arms. As Pauling pointed out, this ambition led to sales of military surplus.

“What do we have going on in the world now?” Pauling queried at the podium.

Wars, a lot of wars. And thousands, tens of thousands of people killed every year in wars…And what does the United States do, and the Soviet Union do, and the Chinese People’s Republic? They all sell advanced military weapons to other countries, the underdeveloped countries, countries that have a lot of money because of oil.

Pauling’s rhetoric had sharpened over the years, and now, before a packed house in Los Angeles, he demanded a change from the military-industrial status quo that had emerged in the wake of the Second World War.

Now we are forced to eliminate from the world forever the vestige of prehistoric barbarism, this curse of the human race, war. We, you and I, are privileged to live at a time in the world’s history, this remarkable extraordinary age, the unique epoch in this history of the world, the epoch of demarcation between the past millennia of war and suffering and the future, the great future of peace, justice, morality, and human well-being. The world community will thereby be freed, not only from the suffering caused by war, but also from hunger, disease, and fear through the better use of the earth’s resources, the discoveries made by scientists and the efforts of human beings through their work. And I am confident that we shall, in the course of time, build a world characterized by economic, political and social justice for all persons and a culture worthy of man’s intelligence.


In 1991, the year following Pauling’s Soka University address, Linus Pauling and Daisaku Ikeda, along with Johan Galtung, the Norwegian founder of the discipline of Peace and Conflict Studies, signed the Oslo Appeal. This document urged the United Nations to require that nuclear member states issue a global, joint Nuclear Test Ban Treaty as well as a Nuclear Non-Proliferation Treaty; outlaw the production and stockpiling of chemical and biological weapons; prohibit the international weapons trade; and sponsor an international conference to discuss the redirection of resources released through disarmament to support development in the Third World.

Subsequently, Linus Pauling received the Daisaku Ikeda Medal for Peace, awarded by Soka Gakkai International in 1992. Later that year, the English translation of his and Ikeda’s dialogue was published in the West under the title of A Lifelong Quest for Peace.

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Visitors at the San Francisco opening of the “Linus Pauling and the Twentieth Century” exhibit, 1998.

Following Pauling’s death in 1994, Ikeda expressed a desire to honor his friend with a travelling exhibition that would be funded by Soka Gakkai’s resources. The exhibition was initially conceived of as a means for educating the public on ideas in chemistry and as a mechanism for introducing children to Pauling as a role model.

As it moved forward, the exhibit shifted toward honoring all facets of Pauling’s career as a humanitarian, activist, scientist, and medical researcher. Once finalized, the exhibit toured the world for six years. Millions of people saw it in Europe and Japan, as well as multiple locations in the United States, including Washington D.C., San Francisco, Boston, and Pauling’s birthplace, Portland, Oregon.

Pauling and Ikeda

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Daisaku Ikeda, 2010

[Part 1 of 2]

“If the people are not misled by false statements by politicians and authorities, they will recognize the need for world peace and their own responsibilities in achieving this goal.”

-Linus Pauling, 1988

In August 1945, Daisaku Ikeda, a resident of Tokyo and the son of a seaweed farmer, witnessed first-hand the devastation that two nuclear bombs wrought upon his homeland. The experience instilled in Ikeda an insatiable yearning to understand and eliminate the sources of war.

In pursuing this ambition, Ikeda studied political science at what is now Tokyo-Fuji University, and committed himself to the pacifist lifestyle of a Nichiren Buddhist. Ikeda’s chosen faith, named after a twelfth-century priest who emphasized the Lotus Sutra as the authoritative text for adherents of Buddhism, was becoming extremely popular among East Asians following World War II. Fundamental to the practice’s message was a strong call to treat others with respect and compassion, recognizing that all will become Buddhas in the end.

Ikeda also joined a new religious organization called the Soka Gakkai, which followed the teachings of Nichiren, and ultimately became the group’s president in 1960. In his capacity as chief executive, Ikeda focused intently on opening Japan’s relationship with China, and establishing the Soka education network of humanistic schools from kindergarten through university. He also began writing a book titled The Human Revolution.

As his tenure moved forward, the Soka Gakkai grew into an international network of communities dedicated to peace and to cultural and educational activities. In 1975, Ikeda founded an umbrella organization known as Soka Gakkai International (SGI) to fund, direct the resources of, and help facilitate communication between the dispersed Soka Gakkai members. In the 1980s, he turned his attentions toward anti-nuclear activism and citizen diplomacy, and it was in this capacity that he came into close contact with Linus Pauling.


Pauling’s first interaction with SGI came in the early 1980s, by which time the non-governmental organization was already actively cooperating with the United Nations’ department of public information to mobilize citizens for mass movements demanding peace. Seeking to increase SGI’s influence in propelling the peace movement, Ikeda decided to initiate communications with Pauling, who was by now splitting the majority of his time at the family ranch in Big Sur, California and the Linus Pauling Institute of Science and Medicine in Palo Alto. It was at the latter location where Ikeda’s associate, Mr. Tomosaburo Hirano, would make contact with and interview Dr. Pauling.

This meeting proved to be the first step in a lengthy “courtship” that involved extensive correspondence between Pauling’s secretary, Dorothy Munro, and Ikeda’s assistant, Hirano. Indeed, more than six years would pass before Pauling communicated directly with Ikeda and, a bit later on, finally meet Ikeda in person.

Over the course of those six years, Hirano met with Pauling for two more interviews, focusing primarily on Pauling’s views on peace, but also, to a lesser degree, on his scientific work. Extracts from these sessions were often published in the Seikyo Simbun Press – the Soka Gakkai’s daily newspaper in Japan – for which Hirano served as associate editor. The pieces typically highlighted Pauling’s work toward nuclear disarmament and were often published in tandem with Ikeda’s release of new strategic proposals bearing titles such as “A New Proposal for Peace and Disarmament” and “Toward A Global Movement for a Lasting Peace.”


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Pauling and Ikeda pictured together in an article published in the Kanagawa Shimbun newspaper, February 2005.

Finally, at the end of 1986, Pauling received a New Year’s card from Ikeda. The following year, during a trip to Los Angeles, Ikeda requested a personal meeting with Pauling, which Pauling obliged. Face to face at last, the two men developed an instant rapport with one another, quickly exhausting the allotted time for their meeting with discussion (aided by a translator) of a wide range of subjects: science, peace, childhood and adult life. The conversation even drifted into Pauling’s hobby of collecting and studying different editions of the Encyclopedia Britannica.

Ikeda was fascinated by Pauling’s warm recollections of major figures such as Albert Einstein, Albert Schweitzer, Bertrand Russell and, of course, Ava Helen Pauling, whose life and accomplishments Pauling cited as having been directly responsible for his peace activism. The two also talked about Pauling’s Nobel Peace Prize lecture, in which he had said that he believed the world had inevitably to move into a new period of peace and reason, that no great world war would again threaten the globe, and that problems should be solved by world law to benefit all nations and people.

In that same lecture, Pauling emphasized that, were it up to him, he would prefer to be remembered as the person who discovered the hybridization of bond orbitals, rather than through his work toward reducing nuclear testing and stimulating action to eliminate war. Nonetheless, Pauling considered the Nobel Peace Prize to be the highest honor that had ever received, in particular because of the onus that it placed upon him to continue that work. By contrast, Pauling felt that his Nobel Chemistry Prize, awarded in 1954, had plainly been earned for work already accomplished.

Over the course of their conversation, Ikeda also learned that being dedicated to peace, for Pauling, meant working toward the prevention of suffering for all human beings. In this, Pauling’s point of view as a humanist matched up well with Ikeda’s Buddhist philosophy. Specifically, Ikeda’s faith taught that one should regard others’ sufferings as their own and should seek out to eliminate it – a principle also expressed in the teachings of Christ, Kant’s Categorical Imperative, and in the Analects of Confucius, and more generally known as the Golden Rule.

Though Pauling was an avowed atheist, Ikeda pointed out that he did not feel his own religion to be an impediment to his rationality – the same rationality that Pauling believed guided his own desire for peace. Rather, Ikeda argued that

Religions must make every effort to avoid both bias and dogma. If they fail in this, they lose the ability to establish a sound humanism and can even distort human nature. The twenty-first century has no need of religions of this kind.

So concluded the long-awaited first meeting between two men of like interests. The communications and collaborations that were still to come will be explored in our next post.

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.

Remembering Richard Marsh

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Richard Marsh, 1960. Credit: Caltech Archives.

At the beginning of this year, on Tuesday, January 3rd, the highly accomplished crystallographer Richard E. Marsh passed away at the age of 94. During his impressive sixty-six-year career at Caltech, Marsh was influenced greatly by Linus Pauling’s work in crystallography, and eventually collaborated with him throughout the 1950s and early 1960s. Colleagues and admirers alike knew Marsh for his rigorous standards in investigating atomic structure, a discipline that resulted in his determination of over one-hundred crystal structures throughout his career and the improvement of at least that many more.

In a Caltech tenure that spanned more than six decades, Marsh also inspired generations of graduates and undergrads alike, teaching valuable techniques in crystallography and instilling in his students the rigor of his own research practice. His course “Methods of Structural Determination” was among the most popular graduate offerings in the Institute’s Chemistry division for a great many years. He leaves behind an impressive legacy for the crystallographers of today.


Marsh, who went by Dick, was born in 1922 in Jackson, Michigan. By the time that he arrived at Caltech as an undergraduate in 1939, Pauling had already helped to established the Institute as among the premiere destinations for budding young crystallographers around the world. In particular, Pauling’s newly published Nature of the Chemical Bond had transformed crystallography from arcane to fundamental.

Though Pauling was certainly well known on campus when Marsh was an undergraduate, it would be another eleven years before Pauling and Marsh formally crossed paths. As a student, Marsh had identified an interest in chemistry, but hadn’t narrowed to a particular focus. He commented later that a technical drawing course at Caltech served as a precursor to his interest in crystallography. He graduated with his BS in applied chemistry in the midst of World War II (1943) and, upon graduation, enlisted in the US Navy, spending the next two years degaussing ships in New Orleans. This is where he met his wife Helena Laterriere, to whom he remained married for nearly seventy years.

Following his discharge, Marsh enrolled in graduate school at Tulane University so that he might remain in close proximity to his fiancée. Most of the courses that he needed were already full at the time of his enrollment, so Marsh signed up for an X-ray crystallography class at the nearby Sophie Newcomb College for women. It was there that he met the teacher who changed his life and cemented his interest in crystallography.

That teacher, Rose Mooney, had previously attempted to enroll at Caltech for graduate studies only to be turned away when she arrived in Pasadena and the administration realized that she was a female. Pauling himself stepped in at this point, giving her a temporary position in his laboratory until she was accepted into the graduate program at the University of Chicago. Her lab at Sophie Newcomb College was quite modest, containing only a Laue film holder and one x-ray tube, but for Marsh it was enough. Inspired, his course was set from then on, though he’d have to travel across the country to continue it.

After marrying Helena on August 11, 1947, Marsh enrolled at UCLA. He later called the 2,000-mile move across the southern United States the beginning of their honeymoon, joking that it was a wedding present to his new bride. At UCLA, Marsh studied crystallography under Jim McCullough and earned his Ph.D. in 1950. Caltech subsequently offered him a post-doctoral research appointment, and he remained at the Institute for his entire career, always in a non-tenured position until his retirement in 1990, when he named an emeritus professor.


In the years immediately following World War II, Caltech was still very much the place to be for crystallographers. Thanks largely to Pauling, who returned to structural chemistry after his own war projects had wrapped up, scientists from all over the world travelled to Pasadena to conduct research and solve structures.

Marsh finally became associated with Pauling in 1950, when he arrived at the Institute as a post-doc. He published his first paper with Pauling, “The Structure of Chlorine Hydrate,” in 1952. A year later, the duo published “The crystal structure of β selenium,” which marked the first time that Marsh issued a correction of someone else’s work. Indeed, over the course of his career, Marsh became increasingly focused on policing the field for errors, always striving for maximum accuracy and precision. Pauling engaged in this work himself from time to time, although the various demands on his attention kept him too busy to make a full-time habit out of it.

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Marsh at the famous Caltech Proteins Conference in 1953. To his right is Francis Crick.

Pauling and Marsh continued to collaborate on a number of other publications related to atomic structure between 1952 and 1955, at which point their interests began to diverge. Nonetheless, the two retained a degree of professional closeness throughout the following decades, often writing to compliment one another on various accomplishments, solicit advice, or suggest future projects. In one instance, Pauling provided the kernel of an idea that resulted in Marsh’s 1982 paper on N, N-Dimethylglycine hydrochloride. Likewise, Marsh helped pave the way for Pauling to publish one of his own articles in Acta Crystallography, where Marsh served as an editor for seven years.

In 1975, presented with the problem of solving of a compound that generates hydrazine from molecular nitrogen, Marsh devised and shared a method for determining the structure. This solution influenced the direction of study into hydrazine formation, creating the opportunity for further study. And although Marsh continued to solve structural problems in the years that followed, he also devoted countless hours – over half his career – to the pursuit and correction of published errors, usually pertaining to inaccurate space groups in important crystal structures. Pauling later described Marsh as the “conscience of crystallography.”

With time, he gained such a reputation that his colleagues in the field were perpetually anxious that they would be “Marshed,” or taken to task, for their errors. Marsh held his colleagues accountable to their calculations and believed firmly in checking a computer’s work, rather than the other way around. He is remembered today as having been responsible for many refinements in crystallographic discipline and for the high standards that make future refinements possible.


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Marsh in 2012. Photo by Rafn Stefansson.

In terms of organizational involvement, Marsh joined the American Crystallographic Association (ACA) shortly after starting at Caltech. Over the duration of his career, he became increasingly active in the group, and ultimately served as its president in 1993. He was also co-editor of Acta Crystallography from 1964-1971.

Marsh’s classroom lectures and his relationships with students were at least as influential as were his publications in crystallography. One colleague, B.C. Wang, recalled that Marsh summoned crystallographers of all stature – be they students, professors, or visiting scientists – to a group coffee at 10:30am every day, to encourage discussion and advancement within the field. Students also remembered him as critical but encouraging, his commitment to student success serving as an inspiration for their own hard work.


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Marsh and Pauling in 1986. Credit: Caltech Archives.

When queried by CRC Press in the early 1990s for his input on future publications, Pauling suggested that the press solicit a monograph from Marsh on the crystal structures that he had corrected thus far, arguing that a volume of this sort might help future crystallographers to avoid these errors. Pauling then wrote to Marsh, inquiring about the total number of crystal structures that Marsh had indeed corrected. Pauling had guessed that Marsh had published fixes for 25 to 30 structures and was surprised to learn that the actual number was between 110 and 120.

Although Marsh didn’t publish this proposed monograph, Pauling’s idea evidently inspired him. In 1995, he authored a substantial article on the subject, titled “Some thoughts on choosing the correct space group.” In the piece, Marsh discussed common types of errors as well as preferable techniques and methodology, including a few tables that documented space group revisions over time.

While at Caltech, Marsh worked closely with Verner Schomaker, another of Pauling’s graduate students. In 1991, the two teamed up to put together a festschrift honoring Pauling’s early work on crystallography. Pauling, a man who, by then, had received basically every award that a scientist can get, was immensely pleased and grateful for this honor.

In 2003, Marsh received the inaugural Kenneth Trueblood Award from the American Crystallographic Association for his outstanding achievements in chemical crystallography. Few other awards could be more fitting for a crystallographer of Marsh’s caliber and commitment. In announcing the prize, the chair of the selection committee identified Marsh as a “rare individual among crystallographers, an outstanding teacher and researcher who has greatly influenced so many students and faculty.” He will be remembered and missed for this indefatigable integrity, dedication, and mentorship.