Monthly Archives: November 2013

Cotton Mather, Onesimus, George Washington, and Variolation

Here are a couple of vignettes that may be particularly interesting to American history buffs. They concern the introduction of variolation to New England during the Colonial Period in North America. A major smallpox outbreak occurred in Boston in 1620, and again in 1702 and 1721. These happened before the advent of Jenner’s smallpox vaccine, in the late 1790’s. Note that Native Americans suffered especially severely from smallpox.

The colonialists initially dealt with smallpox by quarantining individuals who might transmit the disease. However, bear in mind that variolation had been used successfully in China and India since the 11th century to block the spread of smallpox. Variolation is the practice whereby uninfected individuals are inoculated with material from the dried out scabs of individuals who survived a smallpox infection. [Variolation worked because the dried-out scabs on the skin of a smallpox survivor contained virus that had been partially inactivated by that individual’s immune response, as well as by the drying itself. And, the inactivated virus might yet induce immunity in the inoculated recipient.] The practice was inspired by the yet earlier recognition by the Chinese, well before the advent of the germ theory of disease in the West, that individuals experience some illnesses only once in a lifetime. [Remarkably, Thucydides came to the same realization 24 centuries ago in Greece. The reason Thucydides’ observation had no lasting effect on Western medicine is the subject of another tale.]

A transmission electron micrograph of smallpox viruses.  Source: CDC/ Fred Murphy
A transmission electron micrograph of smallpox viruses. Source: CDC/ Fred Murphy

By 1700, variolation had spread from China to India, the Ottoman Empire, and Africa. Lady Mary Wortly Montague, the wife of the British ambassador to Turkey, learned of the practice while in Constantinople, and brought it home to England in 1721. Before that, while still in Turkey, she had her 5-year-old son, Edward, undergo the procedure. Subsequently, in 1721, in England, she also had her 4-year old daughter variolated. Physicians of the royal court were present on that occasion to witness the procedure. English doctors then insisted that the relatively simple process of variolation be preceded by severe bloodletting to “purify” the blood, thereby excluding non-physicians from carrying out, and profiting from the practice.

The story of Lady Montague’s role in introducing variolation to England is rather well known. In contrast, the story of the introduction of variolation into North America is less well known, even though it has several intriguing aspects. So, the earliest known use of variolation in North America occurred during the 1721 smallpox outbreak in Boston. Its use resulted from the efforts of the prominent Puritan minister Cotton Mather, who persuaded a Dr. Zabdiel Boylston to try variolation in order to control the outbreak.

Most interestingly, Mather learned of variolation from his African slave, Onesimus, who had been inoculated as child in Africa, and who was a “gift” to Mather in 1706, from his Boston congregation. Variolation was then being practiced in western Africa, perhaps brought there by caravans from Arabia. So, an enslaved African man played a key role in bringing variolation to North America.

Mather tried to convert Onesimus to Christianity, but, finding him increasingly rebellious, Mather gave Onesimus the opportunity to purchase his freedom in 1721. Onesimus did so by helping Mather purchase another African slave to take his place. However, once freed, Onesimus continued to do chores for Mather and his family. Little else is known of Onesimus’ life.

The most bizarre aspect of this story may be that Mather is best known for his role in promoting the Salem Witchcraft trials. In 1688, he argued that the peculiar behavior of four Boston sisters was the result of witchcraft practiced on them by a washerwoman named Mary Glover. What is more, he argued that the behavior of these sisters should be taken as evidence against the accused during the trials. Yet Mather was also a prolific writer and, incongruously, he wrote extensively on science, as well as religion. Moreover, he acknowledged that his scientific writing was strongly influenced by Robert Boyle’s The Usefulness of Experimental Natural Philosophy. Furthermore, in 1716, following up his observation of differences among various strains of corn, he carried out one of the first recorded experiments with plant hybridization. And, for his scientific accomplishments, in 1713 he was elected as an honorary member of London’s Royal Society. Thus, this man who supported and witnessed the execution of “witches,” was in at least some ways a man of the Enlightenment. And, while Mather had no reservations regarding the morality of slavery, he believed that blacks had souls; actually a liberal view that was contrary to the prevailing views of the day. But, while he was enthusiastically committed to converting black slaves to Christianity, he also strongly held that conversion of slaves to Christianity was not incompatible with their remaining in bondage.

At any rate, Mather urged Boston’s doctors to try variolation, finally succeeding with Boylston. Boylston first tried the procedure on his only son and two slaves; one a child and the other grown. [Interestingly, although history credits young James Phipps as the first subject of Edward Jenner’s smallpox vaccination experiments in the 1790’s, the first vaccine recipient was actually Jenner’s 10-month-old son Edward Jr. Jenner also inoculated several other young children, including his second son Robert, when he was 11-months-old. More on this in another tale.]

Considering the risks associated with variolation (2 to 3% of variolated individuals died from variolation-transmitted smallpox), this practice generated considerable controversy among physicians of the day, with some asserting that it helped to spread, rather than contain the epidemic. In the end, critics of variolation, after observing its overall positive results, came to accept its use. [During the 1721 Boston epidemic, some 6,000 of Boston’s slightly more than 10,000 residents contracted smallpox, and some 14% of the infected individuals succumbed to the disease. In contrast, less than 3% of the variolated individuals died.]

Oddly enough, Mather went against his own Puritan ethic in promoting variolation. The Puritans viewed all afflictions, including smallpox, as part and parcel of God’s plan. What’s more, the debate over variolation between medical professionals and the clergy caused the latter to lose influence over secular matters in eighteenth-century New England.

A related vignette concerns George Washington, whose experiences during the French and Indian War (1754-1763) made him aware of how seriously smallpox might impair the fighting effectiveness of his soldiers. Later, in 1777, during the American War for Independence, and after the loss two major battles against British soldiers, who all had been variolated, Washington required the entire Continental Army to undergo variolation. Moreover, all new recruits had to be variolated immediately upon joining. [These were the days before informed consent.] Also, a political cartoon of the day implies that before Washington ordered the entire Continental Army to be variolated, he first tested the safety of the procedure on his Hessian mercenaries. One in 500 variolated soldiers died as a result of the procedure, but the odds still strongly favored variolation over taking one’s chances with an actual smallpox infection. There is speculation that at least some of Canada (Quebec) would have ended up as part of the United States if Washington had variolated his troops earlier in the Revolutionary War.

And, when did Jenner’s cowpox-based smallpox vaccine first come to be used in the New World? It first came to the attention of New England, and the rest of America, in 1799, thanks to Benjamin Waterhouse, a European educated Boston physician. Waterhouse wrote letters to newspapers throughout New England chronicling the new smallpox control method. Waterhouse not only wrote letters, but also introduced the Jenner vaccine in Boston, using cowpox that Jenner shipped to him by request (on threads dipped in cowpox exudates, sandwiched between glass plates that were sealed in lead). The vaccine could then be transferred from one individual to another by means of a lancet; a practice acceptable at the time because of the much greater danger of smallpox and the limited scientific knowledge of the day. Incidentally, Waterhouse also co-founded Harvard Medical School.

Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis

 The following set of tales primarily concerns the crossing of paths of three rather exceptional individuals; Max Delbruck, Niels Bohr, and Lisa Meitner. What’s more, other heavy hitters of 20th century science and statecraft figure in these vignettes, which also happen to play out in Europe and the United States on the eve of, and during the Second World War.

Since this site is first and foremost an anthology of anecdotes related to virology, Max Delbruck is our focus here. With that in mind, the background is as follows. In the middle 1930s, interest in virology was for the most part medical and agricultural. Essentially all that was known at the time about viruses was that they are smaller than bacteria, that they can replicate only within suitable host cells, and that they are comprised only of nucleic acid and protein. Moreover, recall that nothing was yet known about the chemical nature of genes or how they might be replicated. The structure of DNA was not yet known, and most biologists of the day would have bet that genes consist not of DNA, but of protein. As one might imagine, attempts to account for how protein might be replicated led to rather unsatisfactory models, causing some physicists and chemists of the day to believe that living matter might be governed by as yet unknown physical laws.

At that time, a rather atypical group of investigators, many of whom had little or no knowledge of traditional genetics, biochemistry, or even biology in general, sought to understand the nature of genes. Many were physicists by background and, interestingly, they were primarily motivated by the notion that the study of genes might reveal previously unknown other laws of physics. Important to our story, several of these individuals recognized that since viruses are simple enough to be crystallized, and are comprised only of nucleic acid and protein, yet are capable of replication, viruses might be the ideal focus of their research into the nature of genes. The interest of this odd group of investigators in genes, and their focus on viruses, would lead to discoveries of singular overwhelming importance, not only with regard to viruses, but for biology in general. Indeed, their research in the 1930’s and 1940’s eventually led to the creation of the science known as molecular biology, a high point of which was the discovery of the structure of DNA by Watson and Crick in 1953.

Max Delbruck was perhaps the key player in this atypical group of scientists, which also included Salvatore Luria and Alfred Hershey. Together, these three individuals would comprise the original “phage group.” [Phages, short for bacteriophages, are viruses that replicate in bacterial cells.] Incidentally, James Watson was Luria’s first graduate student. Watson decided to do his doctoral research in Luria’s laboratory, at Indiana University, because he knew that Luria and Delbruck had done phage experiments together and were close friends.2 Watson shared a bench with Renato Dulbecco, another future Nobel laureate (and another story), in Luria’s lab.

Delbruck originally trained as a physicist in Germany during the 1920s, studying quantum mechanics under the guidance of Max Born. Moreover, he interacted with other great physicists of the day, including Wolfgang Pauli, Albert Einstein, and Erwin Schroedinger. In 1931 Delbruck went to Copenhagen for postdoctoral studies with Niels Bohr, and it was actually Bohr who aroused Delbruck’s interest in biology1. Indeed, Niels Bohr was the major scientific influence in Delbruck’s life.

At this point, we might say a word or two more about Bohr, the great Danish physicist who made exceptionally important contributions to the understanding of atomic structure and quantum mechanics. Indeed, Bohr is regarded by many as Einstein’s only intellectual equal. At a scientific conference, when Einstein famously attacked the probabilistic nature of quantum physics, saying “God does not play dice with the universe,” Bohr famously replied, “Einstein, stop telling God what to do.”

Delbruck came back to Germany in 1932 to work as an assistant to Lise Meitner at the University of Berlin, where she had a key research program in nuclear physics. Interestingly, Delbruck’s move to Meither’s lab was largely motivated by his desire to be near to the Kaiser Wilhelm Institutes (today known as the Max Planck Institute for Medical Research); then world-renowned for its biological research.

Delbruck was not Jewish. Even so, in 1937, with the Nazis in power, Germany became intolerable for him, and so he left Meitner’s laboratory, settling in the United States, where he accepted a teaching position at  the California Institute of Technology and, later, at Vanderbilt University.

Meitner was Jewish. However, she chose to remain in Germany, protected by her Austrian citizenship. She continued to focus on her work, while other eminent Jewish scientists, including her nephew Otto Frisch, and Leo Szilard were forced out of their positions and emigrated, if fortunate enough to be able to do so.

In 1940, Delbruck, together with Salvatore Luria and, eventually, Alfred Hershey, formed the “Phage Group,” as noted above, and did their first experiments at the Cold Spring Harbor Laboratory on Long Island, NY. Importantly, the slowly growing Phage Group comprised the first investigators to carry out quantitative experiments on the nature of viruses and their replication. And, as noted above, they were instrumental in the development of the new science of molecular biology.

Returning to Lisa Meitner, shortly after Delbruck left Germany, Meitner went on to discover nuclear fission. Meitner was also the first scientist to recognize that Einstein’s famous equation, E = mc2, explained the source of the tremendous energy released in nuclear fission, as generated by the conversion of mass into energy; an idea actually inspired by a letter to her from Bohr. She and Leo Szilard were also the first (apparently independently) to recognize the possibility for a chain reaction; all necessary prerequisites for the making of an atomic bomb. These accomplishments are particularly intriguing because Meitner, as a Jew, was by then a non-person in Nazi Germany.

After the Anschluss (the annexation of Austria by Nazi Germany in 1938), Meitner’s situation in Germany became desperate. So, she fled Germany for safety in Holland, thanks to the efforts of Dutch physicists who persuaded their government to admit her on her Austrian passport that was no longer valid. In fact, Meitner was lucky to escape from Germany, since Kurt Hess, a chemist and an ardent Nazi, informed the Nazis of her imminent intent to flee. Later, in 1946, she acknowledged, “It was not only stupid but also very wrong that I did not leave (Germany) at once.”

Niels Bohr once again plays a role in our tale, since he found a laboratory in Sweden where Meitner might continue her work, and also secured funding for her from the Nobel Foundation. What’s more, Bohr helped to rescue numerous other refugees from the Nazis, including Felix Bloch, Otto Frisch, Edward Teller, and Victor Weisskopf. Recalling that Frisch was Meitner’s nephew, he and his aunt, together, were the first to articulate a theory of how the nucleus of an atom could be split into smaller parts. And, it was Frisch who named the process “nuclear fission.”

In 1943, having a Jewish mother and learning of his imminent arrest by the Nazis in occupied Denmark, Bohr, aided by the Danish resistance, fled by sea to neutral Sweden. The very day after Bohr arrived in Sweden, he persuaded the King, Gustav V, to give refuge to all of Denmark’s 8,000 Jews. Shortly afterwards, Swedish radio broadcast that       Sweden was offering asylum to the Danish Jews, and their mass rescue then successfully proceeded.

Even in Sweden, Bohr may not have been safe from German agents, who were rumored to be out to assassinate him there. This led to his harrowing escape to Scotland. Bohr was spirited away in the un-pressurized empty bomb rack of an unarmed Royal Air Force Mosquito Bomber. Not hearing the order to switch on his oxygen, he passed out at high altitude. The pilot suspected this and descended to a lower altitude for the remainder of the flight, thereby saving Bohr’s life.

Bohr spent the last 2 years of the war in England and America, where he was associated with the Atomic Energy Project, and then became one of the first and most prescient arms control advocates. Bohr believed it would be a great tragedy if a nation were to deploy its nuclear bomb against a nation that did not have the bomb. On the other hand, he believed that if all nations shared atomic bomb technology, then war might become unthinkable. Thus, he believed that sharing bomb technology with the Russians would prevent an otherwise inevitable breakdown in trust between the wartime allies, as well as a destabilizing post-war arms race. Bohr was prestigious enough to obtain audiences with both Roosevelt and Churchill. However, the politicians saw only the military implications of the atomic bomb. To them, it was simply a bigger and better bomb than all the others. What’s more, Churchill wondered if Bohr might be a Russian agent. Incidentally, Meitner refused an offer to work on the bomb project at Los Alamos, stating “I will have nothing to do with a bomb!”

Getting back to Delbruck, even while he was working with Meitner, his interest was actually on developing quantum mechanical models of genes, an approach inspired by Schroedinger. Afterwards, Delbruck (jokingly?) took indirect credit for Meitner’s discovery of nuclear fission, saying that his waning interest in physics was holding back Meitner’s group, and thus, his leaving enabled the discovery to happen.

Delbruck shared the 1969 Nobel Prize in Physiology or Medicine with Luria and Hershey, for their work on the genetic structure and replication of viruses.

Bearing in mind the times and places of the above episodes, we might add a few more words about Luria, an Italian Jew who studied medicine at the University of Turin (where, incidentally, he first met Renato Dulbecco, who eventually won a Nobel for his foray into animal viruses; work which he began in Delbruck’s laboratory at Cal Tech, and the subject of another story). In 1937, while still in Italy, Luria was awarded a fellowship that he intended to use to work with Delbruck in the United States. However, Mussolini’s fascist Italian regime banned Jews from academic research fellowships. So, having no support, Luria left Italy for France in 1938. Then, in 1940, as German armies invaded France, Luria emigrated to the United States. In New York, physicist, Nobel laureate, and fellow Italian émigré, Enrico Fermi, helped Luria obtain a Rockefeller Foundation fellowship for use at Columbia University. [Fermi, himself, left Italy in 1938 to escape new Italian ‘racial’ laws that affected his Jewish wife Laura. In the United States, with Leo Szilard, he developed the first nuclear reactor.] Luria soon met Delbruck, and they began their collaborative experiments at the Cold Spring Harbor Laboratory on Long Island, NY. When Hershey later joined them, he described the threesome as “two enemy aliens and a social misfit.” Technically, Delbruck and Luria indeed were enemy aliens.

In contrast to Bohr and Delbruck, Meitner was never recognized by the Nobel Committee for her accomplishments. Instead, Meitner’s collaborator, German chemist Otto Hahn, was awarded the 1944 Nobel Prize in Chemistry (actually awarded in 1945) for the discovery of nuclear fission. The reasons for the slight to Meitner may have included her scientific and actual exile; perhaps causing the Nobel Committee to not appreciate her key part in the work. What’s more, Hahn and others may have intentionally downplayed her role. And, while Meitner was bitterly critical of Hahn and other German scientists for not speaking out against Hitler’s crimes, she and Hahn apparently remained lifelong friends. Earlier, when Meitner left Germany, she was virtually penniless. Otto Hahn gave Meitner a diamond ring that he inherited from his mother, for Meitner to use to bribe border guards if necessary. Meitner did not need to use the ring in her escape. It was later worn by her nephew’s wife.

Incidentally, Delbruck’s brother Justus, his sister Emmi, and two brothers-in-law were active in the German resistance against the Nazi regime. The three men were executed for their involvement in the 1944 plot to assassinate Hitler.

Delbruck influenced a whole generation of molecular biologists, both at Cal Tech and at Cold Spring Harbor, where, together with Luria, he established a summer phage course in 1945 that ran there for the next 26 consecutive years. The course did not require any previous preparation and those enrolled ranged from beginning graduate students to already eminent professors, all working side-by-side in the lab. One early taker was the brilliant physicist Leo Szilard. In 1939, after emigrating to the United States, Szilard wrote the famous letter to Franklin Roosevelt, which he convinced Albert Einstein [a German Jew who was visiting the United States when Hitler came to power in 1933 and did not go back to Germany] to sign, that resulted in the Manhattan Project and creation of the atomic bomb.  Working on the Manhattan Project with Enrico Fermi, they together built the first nuclear reactor at the University of Chicago. Incidentally, in 1930, Szilard and Lisa Meitner taught a seminar together in Berlin on nuclear physics and chemistry. And, in 1933, Szilard and Lisa Meitner were the first to conceive of a nuclear chain reaction, as noted above.

Aaron Novick, who eventually became a major molecular biologist, was a budding physicist in 1943, working on the Atomic Energy Project under Szilard at the University of Chicago. He relates how his transformation to a biologist came about, as follows. “One Spring evening in 1947, as we were leaving a meeting of the Atomic Scientists of Chicago, Szilard approached me and asked whether I would care to join him in an adventure into biology. Despite his caution to think his proposition over carefully, I accepted immediately… [My note: Szilárd’s scientific interests switched to molecular biology because of his revulsion over the use of atomic weapons.]…Szilard proposed that we get started in Biology by taking the Cold Spring Harbor phage course that had been recently started by Max Delbruck…It was evident to me that Szilard regarded Delbruck highly. Usually Szillard listened to people only as long as they had something to say that interested him and made sense. This meant that he often turned away in the middle of a conversation. But whenever Delbruck was talking, he stayed to listen.”3

By 1950, Delbruck’s interests began to turn from phage and genes to sensory physiology. Although the major breakthroughs of molecular biology (e.g., the structure of DNA, messenger RNA and the mechanism of protein synthesis, the genetic code) were yet to come, Delbruck was by then confident that biological self replication would be understood without the need to invoke new natural laws. So, he was ready to delve into a new scientific frontier. Nevertheless, Delbruck continued to be a major influence on molecular biology via the researchers who cut their teeth in the Cold Spring Harbor Phage Course or at Cal Tech.

I find these related anecdotes to be exceptionally intriguing. A fantasy is that I might one day participate in the creation of a screen play based upon them.

  1. A Physicist Looks at Biology; Max Delbruck’s chapter in Phage and the Origins of Molecular Biology, J. Cairns, G.S. Stent, and J.D. Watson [eds.] Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1966.  Note that this essay was written by Delbruck in 1949, 4 years before the structure of DNA had been solved. Thus, it reveals Delbruck’s seminal thinking regarding the possibility of living systems being accounted for by as yet unknown laws of physics, and his indebtedness to Niels Bohr.
  2. Growing Up in the Phage Group; James Watson’s chapter in Phage and the Origins of Molecular Biology, J. Cairns, G.S. Stent, and J.D. Watson [eds.] Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1966.
  3. 3.      Phenotypic Mixing; Aaron Novick’s chapter in Phage and the Origins of Molecular Biology, J. Cairns, G.S. Stent, and J.D. Watson [eds.] Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1966. 

The Phage in the Letter

Here is a favorite story of mine that I first heard when I was a graduate student in the mid 1960’s. The major protagonists are Sidney Brenner, who was one of the giants of the “golden age of molecular biology,” and Norton Zinder, also one of the top researchers of the day. Brenner was the first molecular biologist to propose the idea of a messenger RNA, a concept validated by experiments he later did with Mathew Meselson and Francois Jacob. Zinder’s major contributions included the discovery that a bacteriophage can transfer bacterial genes from one bacterial cell to another, a phenomenon referred to as “transduction.” And, apropos this anecdote, Zinder also isolated the f2 bacteriophage, the first bacteriophage known to contain a genome composed of RNA, rather than DNA. [In 1956, Heinz Fraenkel-Conrat at Berkeley, and Gerhard Schramm at Germany’s Max-Planck-Institute for Virus Research, independently discovered that the genome of tobacco mosaic virus is comprised of RNA rather than DNA. Each had found that rubbing the purified RNA of TMV—but not its protein— on wounded tobacco leaves, gave rise to a crop of complete virus particles. Thus, they became the first researchers to demonstrate that RNA can serve as the genetic material of a virus. ]

Bearing in mind how little was known in 1960, when Zinder isolated bacteriophage f2; the discovery of RNA phages had great potential for use in the study of fundamental molecular processes, such as protein synthesis, including its initiation and termination. Clearly, there were good reasons why molecular biologists of the day, including Brenner, wanted to obtain their own samples of f2 phage. So, as the legend goes, Brenner, among others, requested a sample of f2 from Zinder. And, Zinder wrote back to all, saying that the phage was not available.

Zinder may have thought that Brenner wanted the phage to study RNA replication, a topic that Zinder wanted to keep for himself. Now, here is the delightful part of the story. Knowing how carefree researchers can be in the laboratory, Brenner is said to have dipped Zinder’s letter in a culture of E. coli (the f2 host), thereby readily growing up a stock of f2 for himself.

Amusing as this story might be, the actual facts, at least according to a 1997 article by Brenner1, are as follows. First, after Zinder isolsted f2 phage from a New York sewer, he indeed declined to distribute the phage to the large number of researchers requesting it. Second, Brenner’s reason for wanting f2 was not to use it to work on RNA replication, but instead to use it to test bacteria for the presence of a sex factor. The bacterial sex factor is a gene that encodes a so-called pilus, which is present on male bacteria, enabling them to transfer genes to female bacteria. It also is the bacterial “organ” via which RNA phages enter bacterial cells, thus explaining Brenner’s stated interest in f2. [While it might be thought that f2 can only infect male bacteria, interestingly, male bacteria that are infected with f2 can transfer the virus to female bacteria via their pili. Thus, even bacteria have sexually transmitted infections.] Third, while Brenner may not have isolated f2 from Zinder’s letter, he indeed recommended a similar procedure to several other researchers. Brenner also confesses that he might have added to the original myth by hinting that the story actually might be true. In reality, Brenner isolated many RNA phages himself by taking sewerage from the Cambridge, Massachusetts, sewer treatment plant and plating it on bacteria expressing a sex factor.

Micrograph of an F-pilus emerging from an E. coli cell that is covered with icosahedral MS2 phage particles.  At the end of thepilus, a filamentous fd phage has attached itself. The thicker thread emerging at the right is a bacterial flagellum. Figure 6.11, page 188, From Virology: Molecular Biology and Pathogenesis, by Leonard C. Norkin, ASM Press, 2010.

While Brenner’s work as a molecular biology pioneer may have justified a Nobel Prize, he received the award in 2002 for his later studies of the nematode Caenorhabditis elegans, in which his research group traced the fate of each cell from the zygote right through to the adult worm. Their work established C. Elegans as a model system that is now studied in hundreds of laboratories all over the world.

1Brenner, S. 1997. Bacteriophage Tales. Current Biology 7:R736-737.