Tag Archives: holocaust

The Remarkable Journey of Medical Genetics Pioneer, Arno Motulsky

Dr. Arno G. Motulsky, recognized for having pioneered the field of “pharmacogenetics”—the genetic basis for differences in the way individuals respond to drugs—passed away on January 17, 2018 in Seattle, at the age of 94. Since Motulsky was not a virologist, his passing is noted here not for his scientific contributions but, rather, for his improbable achievements against very long odds and, especially, for the remarkable journey from which this story began—a journey which brings to mind a current issue before the public. It began as follows.

Dr. Arno Motulsky in his Seattle apartment in 2014. Credit Clare McLean/University of Washington

1938 saw a dramatic increase in violent anti-Jewish acts by the Nazi regime in Germany. In May 1939, 916 passengers, including 910 German Jews seeking to escape from the Nazis, were aboard the SS St. Louis; a liner of the Hamburg-America Line, which was bound for Cuba. Hundreds of thousands of other German Jews would not be able to get out.

Each of the passengers on the St. Louis had a visa from the Cuban government that was issued before the ship departed from Germany. However, unbeknownst to the passengers—but known to the shipping line—the President of Cuba, Federico Laredo, had invalidated the visas the day before the ship sailed. Thus, when the St. Louis arrived in Havana Harbor, the Cuban government would not allow the passengers to disembark. Instead, the Cuban authorities attempted to exploit the refugees’ situation in order to extort bribes from them. These bribes began at $500 a person and rose to $1,000,000! All the while the ship sat within yards of the shore.

Cuba had been practicing this sort of extortion before the incident involving the St. Louis. Manuel Benitez Gonzalez, the Director-General of the Cuban immigration office, routinely sold landing documents for $150 or more and, according to U.S. estimates, had amassed a personal fortune of $500,000 to $1,000,000. Eventually, Benitez’s corruption would lead to his resignation. However, corruption was not the only factor working against the refugees. Many Cubans saw them as competitors for scarce jobs. Moreover, Cuban sympathy for the refugees’ plight was also tempered by xenophobia and antisemitism. [News reports of the impending sailing of the St. Louis triggered anti-Semitic demonstrations in Cuba even before the ship left Germany.]

As the St. Louis sat at anchor in Havana Harbor, the American public raptly followed daily media accounts of the refugees’ plight. And despite urgent appeals from American sympathizers (non-Jewish as well as Jewish), the U.S. State Department and the White House decided not to intervene on behalf of the refugees. President Franklin Roosevelt did not answer telegrams from the refugees on the ship. The State Department did respond, wiring back to the passengers that they must “await their turns on the waiting list and qualify for and obtain immigration visas before they may be admissible into the United States.”

Roosevelt had the power to issue an executive order that would have allowed the St. Louis’ refugees to enter the United States. He had, in fact, permitted 15,000 German and Austrian Jews, who were in the United States on visitor’s permits, to stay, saying: “It would be a cruel and inhuman thing to compel them to leave here” for Germany.   

Why then did Roosevelt and the State Department abandon the refugees on the St. Louis? American popular opinion, which was opposed to accepting more new arrivals, was a key factor. Indeed, about 80% of Americans were against easing immigration restrictions. A key reason was that the depression left many Americans out-of-work. Consequently, many were fearful of foreigners becoming competitors for scarce American jobs. Antisemitism, isolationism (in the years after World War I, many Americans were staunchly against the U.S. being drawn into European affairs), and xenophobia were no doubt factors as well.

The National Origins Act of 1924 permitted only a fraction of would-be emigres from Germany to enter the United States. The quotas that were set on countries were intended to favor “desirable” immigrants from Northern and Western Europe, while limiting less “racially desirable” immigrants, such as Southern Europeans, Eastern European Jews, and people born in Asia and Africa. Yet anti-German sentiment may have led American immigration officials to allow only one fourth of the German quota to be filled. Also note that three months before the St. Louis sailed to Cuba, the U.S. Congress let die a bill that would have admitted 20,000 Jewish children from Germany above the existing quota.

Critics contend that despite the political pressure on Roosevelt, he might have done more to raise public sympathy for the plight of the refugees. Moreover, once the United States was in the war, and the U.S. government became aware of Hitler’s intent to annihilate all Jews in Germany and in German controlled areas, the government tried to withhold that information from the public. And as the facts about the murder of the European Jews—concentration and extermination camps—leaked out, and despite pleas from Jewish leaders in Warsaw and elsewhere in Europe, Roosevelt would not act to impede the extermination program (e.g., by ordering the bombing of Auschwitz and the rail lines to it). Instead, Roosevelt maintained that winning the war was the only way to save the refugees, and winning the war was the absolute priority.

Barriers to Jewish immigrants were also in place across Latin America. [Note that the British refused to consider Palestine as a solution to the Jewish refugee problem.] Thus, Columbia, Chile, Paraguay, and Argentina rejected appeals from the Joint Distribution Committee (JDC, the major Jewish agency for relief overseas) for haven. And, when the JDC could not meet a deadline set by Cuba for the payment of ransoms, the St. Louis was forced to leave Havana Harbor. Remarkably, the German captain of the St. Louis, Gustav Schröder (who had been unaware of the Cuban government’s duplicity before the St. Louis sailed), appealed to the United States for haven. But his personal pleas were unheeded. What’s more, as the St. Louis sailed past Miami and the Florida coast, U.S. Coast Guard ships made certain that none of its passengers might escape to freedom. So, the St. Louis turned back to Europe, with sixteen-year-old Arno Motulsky among its passengers.

The German liner St. Louis being denied entrance to Havana, Cuba, in June 1939. Dr. Motulsky was aboard the ship with his mother and siblings when it was sent back to Europe. Credit Associated Press

But the St. Louis did not return to Germany. The JDC had arranged with Great Britain, France, Belgium, and the Netherlands for each of these countries to take one fourth of the refugees. Still, only the 288 refugees admitted to Great Britain would be safe, since the Nazis would overrun the other countries within months. Only a few would survive the Holocaust.

Motulsky was among the refugees who disembarked from the St. Louis in Belgium. He then spent a year in internment camps in Vichy France, where many other detainees died from starvation or typhoid. He reached the United States in June of 1941; ten days before his 18th birthday. His account of his flight to freedom, in his own words, is as follows:

“…By early 1939, my parents realized we would need to leave Germany. My dad had a brother in Chicago, so we hoped to go there, but in order to get out of Germany and into America, one needed a visa, which required a quota number that took a while to come up. So my father went to Cuba, where immigration permits were available, with the idea that we would join him later in Chicago. But over the next few months, as the situation deteriorated in Germany, my parents decided it would be best for my mother and brother and sister and me to join my father in Cuba and go to Chicago later.

We left Hamburg in May 1939, on a ship named the St. Louis. There were almost a thousand Jewish refugees on board. The voyage from Hamburg to Havana was normal. But before we could disembark in Havana, the Cubans declared our permits void and refused to let us land. The ship was German, but the captain, Gustav Schröder, was very sympathetic to us and sailed all over the Caribbean in search of a friendly port. Of course, we asked to land in America, but were denied. When we sailed close to Miami, US Coast Guard cutters and planes shooed us off.

So ultimately the ship had to return to Europe. I was 16, so still a little naive, but many of the passengers had been interned previously and knew what awaited us on our return. Some attempted suicide by jumping overboard. Telegrams were sent all over the world asking that we be allowed to disembark anyplace other than Germany. Miraculously, a few days before we would have arrived back in Germany, four other countries—England, France, Holland, and Belgium—each agreed to take one-fourth of the passengers. By luck of the draw, my mother and brother and sister and I were assigned to Belgium. So in June 1939, I started high school in Brussels.

Eleven months later, on May 1, 1940, my dad got his visa to move from Cuba to the US and went to Chicago. On the same day, our US visas came through as well. But by May 10, we hadn’t yet gotten out of Belgium, and the Germans invaded. Leaving was impossible. Since I was now 17, I was arrested by the Belgians as an enemy alien—ironically, as a German—and sent to an internment camp in France. As the Germans invaded France, we prisoners were moved further and further south, until we ultimately were interned in a camp in the Pyrenees, in Vichy-controlled France. The Vichy French, who collaborated with the Germans, sent the ethnic Germans back to Germany and kept the Jews interned. The internment camps had no food or sanitation. Many prisoners died, most from typhoid or starvation.

About ten months later, those of us with US visas were allowed to go to another camp, near Marseilles, where there was an American consulate. My visa had expired, but I pleaded for its renewal. It was ultimately granted, and in June 1941, ten days before my 18th birthday, I left France legally, crossed Spain into Portugal, and sailed from Lisbon to America. Ten days later and I wouldn’t have made it, because Franco did not allow males 18 or older to pass through Spain. A few months later, the Vichy French turned over all their internment camps to the Gestapo.

In August 1941, I arrived in America and joined my father in Chicago. Two years later, we learned that my mother and brother and sister had also survived. With the help of Belgian friends, they had crossed illegally into neutral Switzerland, where they were allowed to live unharmed until the end of the war. My family reunited in Chicago in early 1946.”

In Chicago, in 1942, 18-year-old Motulsky was examined on material he learned in the informal classes taught in the internment camps in France, and was then granted a high school certificate. Motulsky then enrolled in evening classes at Central YMCA College (which later became Roosevelt University) in Chicago, while working at a job during the day. He met his future wife, Gretel, in his English class at the college. He notes that Gretel was the better English student because she survived the war in England and America after leaving Germany in 1938. They were married in 1945.

Remarkably, in 1943, Motulsky was accepted by the medical school of the University of Illinois in Chicago. He also became a U.S. citizen, joined the Army, and was assigned to a specialized program at Yale for rapid training of young physicians. During his year at Yale, Motulsky completed the premedical courses that he still was lacking. More importantly, he also “took genetics with Donald Poulson and was hooked forever.”

In 1944 Motulsky served briefly as an orderly at an Army hospital near Boston, before returning to medical school at the University of Illinois, as a private first class. He was released from the Army in 1946, finished medical school in 1947, and began his residency in internal medicine at Chicago’s Michael Reese Hospital; supported by a fellowship in hematology. Under his fellowship mentor, biochemist and hematologist, Karl Singer, Motulsky began his foray into research, investigating hereditary hemoglobin disorders.

In 1951, the Korean War broke out and Motulsky was again in the Army; this time at a new hematology research unit at Walter Reed Hospital in Washington, DC. “At Walter Reed, we studied hemolytic anemias that might explain problems encountered by our soldiers… Singer had encouraged me to think about biochemical mechanisms, and here were genetic diseases, for which mechanisms could be studied to the direct benefit of patients.”

In 1953 Motulsky joined the faculty at to the University of Washington in Seattle, where he taught internal medicine and specialized courses in hematology. That same year, Watson and Crick determined the structure of DNA, rousing Motulsky to slip what he called “bootleg medical genetics” into his hematology lectures. In 1957 he founded the Division of Medical Genetics at UW; one of the first such divisions in the United States. [The Division of Medical Genetics at Johns Hopkins opened the same year.] But, before that, to broaden the scope of his knowledge, Motulsky spent eight months in the human genetics unit of Lionel Penrose at University College London. “Penrose’s department was the best in human genetics in Europe, including, in addition to Penrose himself, J.B.S. Haldane… People were very critical and helped me recognize excellent work.” Concurrently, Motulsky became interested in what is now called pharmacogenetics—”that is, differential reaction to drugs among people based on their genotypes.”

This blog post was meant to recount Motulsky’s remarkable personal journey during the early years of his life and career. Nonetheless, Motulsky’s considerable scientific contributions also need to be noted, if only briefly—in particular, his analyses of the genetic predisposition to a broad assortment of conditions, including heart disease, blood disorders, colorblindness, infections and immunity, hypertension, and alcoholism (for a concise account of his achievements, see his short autobiography referenced below). It is a good story. For now, note the comments of Francis Collins—a geneticist, and the director of the National Institutes of Health—which Collins made after Motulsky’s passing. “The relationship between heredity and the response to drug therapy — nobody was thinking about that until he started, 60 years ago. He anticipated it decades before science made it possible to get the answers that he dreamed of.” Moreover, “There were very few medical centers that considered genetics as being all that relevant to human medicine. It was more a study of fruit flies and mice, not humans.” Also note the comment of Claire King, Motulsky’s colleague at the University of Washington (and reporter of his autobiography), who discovered the role of certain genetic mutations in breast cancer. Because of Motulsky’s work in medical genetics, “the field is now integrated into every other field of medical practice and has become the soul of precision medicine.”

Motulsky ends his autobiography as follows: “Throughout my career, I have very much enjoyed the practice of medicine. Until I was 70 years old, I was an attending physician in general internal medicine. The human contact, to be able to help people, is enormously rewarding. And I always learned something. I was stimulated to ask new questions by seeing things that I hadn’t previously thought about. And with respect to medical genetics in particular, I know of no other field in science and medicine that is as fascinating. Medical genetics is closer to science than most specialties in medicine. It reveals exciting new biological phenomena. It has social implications and historical implications and ethical implications. I cannot imagine having done anything more exciting for the past 70 years.”

References 

Dallek, R. Franklin Roosevelt and American Foreign Policy, 1932-1945. Oxford University Press. 1979.

Berenbaum, M. The World Must Know: The History of the Holocaust as told in the United States National Holocaust Memorial Museum. Little, Brown and Company, 1993.

Gradyjan, D. Arno Motulsky, a Founder of Medical Genetics, Dies at 94. Obituary, N.Y. Times, January 29, 2018

Motulsky, A. G. (as told to Mary-Claire King). 2016. The Great Adventure of an American Human Geneticist. Annual Review of Genomics and Human Genetics 17:1-15. https://doi.org/10.1146/annurev-genom-083115-022528

Addendum:

Several posts on the blog feature individuals whose lives were impacted in major ways by World War II and the Holocaust. In particular:

The Life and Legacy of George Klein: Cancer Virus Pioneer and Witness to the Holocaust, May 4, 2017.

Gunter Blobel: Nobel Laureate Best known For the Signal Hypothesis of Protein Targeting, February 22, 2018

The Converging Lives of Jacques Monod, Francois Jacob, Andre Lwoff, and Albert Camus in Wartime France, March 27, 2017

 

 

Dr. Arno Motulsky in his Seattle apartment in 2014. Credit Clare McLean/University of Washington
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The Life and Legacy of George Klein: Cancer Virus Pioneer and Witness to the Holocaust

George Klein, professor emeritus of tumor biology at the Karolinska Institute in Stockholm, where he worked with his wife Eva from the very beginning, passed away on December 10, 2016, at the age of 91. Klein was best known for discovering that Epstein-Barr virus (EBV)—the herpesvirus now known to cause infectious mononucleosis—causes two human cancers, Burkitt’s lymphoma and nasopharyngeal carcinoma. Moreover, Klein discovered that EBV triggers Burkitt’s lymphoma by facilitating a chromosomal translocation of the cellular c-myc oncogene, resulting in its constitutive expression. Klein also played pioneering roles in developing the concept of tumor-suppressor genes, and in opening the field of tumor immunology. Klein’s key discoveries are summarized below. But, first, Klein, like several other protagonists in these tales, was profoundly affected by events of the Second World War, and by the early days of the Cold War that followed.

From an announcement for a 2015 symposium at the Karolinska Institute, honoring George and Eva on the occasion of their 90th birthdays

George Klein’s Jewish family moved from Eastern Slovakia to Budapest in 1930. Nineteen-year-old George was working as an assistant secretary to the Jewish Council in Budapest when Nazi Germany began its occupation of Hungary in March 1944. Because George had been working for the Jewish Council, in April 1944 he chanced that to see the Vrba-Wetzler Report, known at the time as the “Auschwitz Report.” It was written by, and was secretly transmitted to the Jewish Council by Rudolf Vrba and Alfred Wetzler, two escapees from Auschwitz. It described firsthand the fate of Jews arriving at Auschwitz, and was meant to warn Hungary’s Jews, so that they might hide from, or rebel against their Nazi oppressors.

The Auschwitz report was not publicized in Hungary for reasons explained below. However, George’s supervisor at the Jewish Council gave him permission to tell his relatives and friends of what the report revealed. But they, like most Hungarian Jews, could not believe that such atrocities could actually be taking place. [During May, June, and July 1944, 437,000 Hungarian Jews were deported to Auschwitz; to be “resettled” according to the Nazis. But, in fact, most were murdered in the gas chambers.]

Klein was arrested and pressed into forced labor by the Nazis. Afterwards, since he knew the contents of the Auschwitz Report, he fled when he was about to be ordered to board one of the deportation trains to Auschwitz. Having escaped from almost certain death, he lived underground until January 1945, when the Russian Army liberated Budapest.

Forty-three years later, Klein was watching, Shoa, the monumental (nine-hour-long) French documentary film about the holocaust. Watching the movie, Klein chanced to see a man named Vrba (one of the six principal holocaust witnesses in the film) describe his experiences as a prisoner in Auschwitz. The events that Vrba recounted horrified Klein.

Later in the film, as Vrba described his escape from Auschwitz, Klein suddenly realized, “the report I had been given to read under a promise of secrecy in Budapest in May 1944—at the age of nineteen and at a time when deportations from the Hungarian countryside were at their peak—was identical to the Auschwitz Report of Vrba and Wetzler (1).”

Next in this remarkable tale, Klein decided to try to find Vrba, to “tell him of what enormous help his report had been to me. If I had not known what was awaiting me at the other end of the train trip, I would never have dared to risk an escape. It was not difficult to find Vrba, for it turned out that we were scientific colleagues. He is a professor of neuropharmacology in Vancouver, and I am now (in the Spring of 1987) sitting in a comfortable armchair in the faculty club at a Canadian university, talking with someone who, at first glance, seems quite ordinary. He impresses me as being relaxed and jovial. By now I have also read his book (Escape from Auschwitz, 1964), and I am aware that he has survived more death sentences than anyone else I have ever met (1).”

Vrba (1924–2006), was indeed a professor of pharmacology at the University of British Columbia; a position he held from 1976 until the early 1990s. Note that he and Wetzler were the first prisoners ever to escape from Auschwitz. Vrba’s real name was Walter Rosenberg. Rudolf Vrba was the nom de guerre he used after joining the resistance in his native Czechoslovakia. Afterwards, he made the change legal.

The horrors of the holocaust remained an obsession for Klein, although he was uncertain as to why that was so. “Was it to honor my murdered family, my murdered classmates? Or was it rather to steel myself against the darkest side of our human heritage?” In any case, Auschwitz and the holocaust were the main topics of conversation when Klein met with Vrba.

Vrba took Budapest’s Jewish Council to task for not widely broadcasting the warnings in the Auschwitz Report. He, and others, have alleged that Dr. Kastner, a well-known Zionist leader in Budapest, decided to keep the Report secret, in return for a promise from the Germans to allow sixteen-hundred people, as selected by Kastner, to safely emigrate from Hungary. Klein retorted that he knew Kastner from his work for the Jewish Council, and considered him to be a hero, because he had rescued many, while others tried to rescue only themselves or their own families. [In 1957, Kastner was murdered in Israel by a young man whose family was exterminated by the Nazis. Kastner remains a controversial figure to this day.]

Klein and Vrba next discussed whether dissemination of the Auschwitz Report might have caused Budapest’s Jews to revolt against the Nazi program of annihilation.  Klein argued that of the dozen or so people that he warned, no one believed him. Vrba countered, “You were a mere boy. Why would anyone believe what you were saying? The Jews would certainly have believed their responsible leaders (1).” Nonetheless, Vrba conceded that even the prisoners at Auschwitz were in denial of what they could see with their own eyes: “…prisoners, who knew full well that no one ever returned from the gas chambers, repressed such knowledge as they themselves lined up for execution in front of the chamber doors.”

Klein asked Vrba how he is able to live and function in Vancouver, a pleasant and friendly place, where no one has the slightest concept of what he endured: “…you must go back constantly to those days. You are called in as a witness at trials of old Nazis or their followers, people who claim that the holocaust never happened. You try to describe something that cannot be described in any human language, you try to explain the incomprehensible, you want people to listen to something they do not want to hear (1).” Vrba, in fact, never did reveal his Auschwitz experience to his colleagues. Vrba explained: “What would have been the use? No one who has not experienced it can understand.” Their conversation went on for almost ten hours. Afterwards, they parted like old friends, despite any differences in their views.

In the Fall of that year, Klein was reunited with Vrba in Paris, together with another newfound friend, German scientist Benno Muller-Hill. In 1966, Muller-Hill was a graduate student in Walter Gilbert’s Harvard laboratory, when he purified the lac repressor; the first genetic control protein to be isolated. Muller-Hill then began a second career lecturing and writing about the role of Nazi doctors and scientists in the holocaust. Klein met Müller-Hill for the first time at a meeting at the Institute for Genetics in Cologne, and the two immediately developed a close friendship.

Muller-Hill was in Paris to visit colleagues at the Pasteur Institute, as well as to meet Vrba. Klein was visiting Paris after attending a scientific meeting in Lyon. Vrba was in Paris at the invitation from the French radio service to refute claims of the ultra-right French leader, Jean Marie Le Pen, that the Nazi gas chambers never existed, and that if the Nazis indeed had any intent to annihilate the Jews, it was merely one of many episodes of the war. [Marine Le Pen, currently a leader of France’s ultra-right National Front, and a candidate for the presidency of France, is Jean Marie’s daughter. She was recently taken to task for denying that French officials and police were complicit in the Nazi roundup of more than 13,000 French Jews in July 1942 (they were later deported to Auschwitz). Le Pen also calls for the deportation of all immigrants from France; a stance that mainly targets Muslims.]

Klein and his two companions ambled about Paris on a beautiful Fall afternoon. They strolled around the Luxembourg Gardens, then continued along the banks of the Seine, turned toward the Latin Quarter, and then stood before the façade of Notre Dame. Yet their minds were elsewhere. “Vrba suggested that we visit the holocaust memorial behind Notre Dame…That walk of only a few minutes took us from the noisy tourist crowd to the silence of the museum’s rooms, where you feel alone and isolated among the symbolic chains and barbed wire. A faint glow of sunlight came in through the narrow openings in the wall. We were surrounded by the voices of the victims…We were all completely speechless. Even Vrba’s macabre sense of humor and his sharp sarcasm had fallen silent for the moment (1).”

After they exited from the memorial, they sat down in a small bistro, where Klein asked his two companions whether German scientists and doctors were actual architects of the holocaust or, instead, merely passive followers. “Benno had concluded from his exhaustive documentation that, contrary to what many wanted so desperately to believe, the ‘euthanasia programs’…and the horrible human experiments… could not be ascribed to a small minority of madmen, opportunists, or charlatans. On the contrary, they had been carried out by quite ordinary and in some instances, eminent physicians and scientists… He (Verba) thought … that would not explain why so many apparently ordinary people took part in the murders without showing any signs of remorse, or how the annihilation program could have been carried out with such efficiency… The discussions between Benno and Vrba continued for several hours (1).”

The day became even more notable later, since Klein had arranged for the threesome to have dinner that evening with Francois Jacob. After a glass of sherry in Jacob’s Latin Quarter apartment, the foursome went to a small restaurant around the corner.

Francois Jacob, and fellow Pasteur Institute scientist Jacques Monod, were awarded Nobel Prizes for their work together on the regulation of lactose metabolism in E. coli (2). More apropos the current episode, Jacob and Monod each received France’s highest military honors for his service during the Second World War—Jacob for his heroism serving with the Free French forces, and Monod for his heroism in the Resistance (2). Yet Jacob’s harrowing escape from Nazi-occupied France at 19-years in age, and his wartime exploits as one of Charles De Gaul’s most highly decorated volunteers, were barely known to his three dinner companions.

At first, Klein was somewhat worried that his friends might not like each other. Jacob often found conversation to be difficult; partly because the thousands of pieces of shrapnel that he carried in his body from the war, made it hard for him to sit comfortably. [Jacob’s wartime wounds prematurely ended his surgical career, and led him to turn to a career in science (2).] But, the get-together didn’t go badly at all.

Conversation eventually turned to the issue of holocaust deniers, as well as to those who would put the past completely behind them. As they talked, the incongruity of the scene suddenly struck Klein. They were sitting in a “first-class Parisian restaurant, surrounded by elegant people, having a very nice dinner in the best French tradition.” “…why did the three of us, with Jacob listening, choose to spend that beautiful Saturday in Paris compulsively focusing our attention on the black birds? We were all citizens of free countries, living well in peaceful times. Were we haunted by feelings of guilt toward the dead? Were we afraid that the whole experience would recur if we let go? We knew that the wide and relentless river of history is rarely influenced by knowledge of the past. In no more than one or two generations, archives of extreme horror turn into scraps of faded paper, with no more influence than dried leaves. I suddenly felt that we were like a traveler with a fear of flying, forcing himself to stay awake and keep his seatbelt buckled during the entire flight, obsessed with the idea that the plane would surely crash if he were to fall asleep. But perhaps we had other motives. Perhaps we wanted to feel a solidarity with each other by selecting a more or less taboo subject for our conversation, one avoided by most others. Or did we try to perform a kind of autopsy, using our brains to understand what human minds are capable of at their worst? Have we appointed our brains to serve as the pathologist and the cadaver at the same time?”

The above recounts only a small sampling of Klein’s conversations with Vrba, Muller-Hill, and Jacob, during their day together in Paris. For more, see reference 1.

In January 1945, 19-year-old George Klein emerged from the Budapest cellar where had been hiding during the last weeks of the German occupation. He gazed on the dead soldiers, civilians, and horses that were frozen in the snow, and was struck by the thought that he had survived, despite the likelihood that he would have ended his 19 years in a Nazi gas chamber or a slave labor camp. However, with the city now in Russian hands, George faced a new threat to his freedom; the Russian patrols that were exporting young Hungarians to labor camps in Russia.

Mindful of the danger on the streets, George was yet eager to begin his medical studies. So, he cautiously dodged the Russian patrols as he made his way to Budapest’s medical school, only to find war-torn deserted buildings and dead soldiers there.

Undeterred by the situation in Budapest, George and a friend set out to Szeged, with the hope of attending the medical school there. The journey of 160 miles took the pair five days, by way of a variety of vehicles, including a Russian military truck. In any case, they were admitted to the Szeged university on the same day that they arrived. And while the school was a shadow of its former self, with all the professors having fled to the West, to George, it was a “previously forbidden paradise (3).”

George spent two years in Szeged, and then returned to Budapest when the University reopened there. Back in Budapest, George fell “desperately” in love with Eva Fisher, a fellow medical student. [George describes their whirlwind romance in reference 3.] George now faced a dilemma. Before he met Eva, he finalized plans to visit Stockholm (under the sponsorship of the Jewish Student Club there). But going to Stockholm would mean leaving Eva behind, under conditions in which travel back into Hungary could be risky. Nonetheless, George went to Stockholm, with Eva believing she would never see him again. Yet the trip would be a defining experience for George and, eventually, would be important for Eva too. In Stockholm, George would learn of, and be riveted by the research of renowned cell biologist Torbjörn Caspersson, at Stockholm’s Karolinska Institute.

Caspersson’s research so enthralled George that he diligently pressed Caspersson for a junior research assistantship in his laboratory. But once George had been accepted by Caspersson, he viewed his situation with a “mixture of ecstatic happiness and enormous anxiety.” “I knew virtually nothing…I was halfway through my medical studies…I was desperately in love with a girl whom I had only known during a summer vacation of eight days and who was on the other side of an increasingly forbidding political barrier (3).”

Despite these misgivings, George knew that his future lay in Sweden, rather than Hungary. He had been accepted into Caspersson’s laboratory, and Hungary was falling increasingly under totalitarian Soviet domination. But Eva was still in communist Hungary. So, George risked returning there with one goal; to marry Eva, and then to leave Hungary for good. “The reunion with Eva confirmed what we both already knew: we wanted to live and work together (3).”

But George and Eva didn’t have the necessary documents to get married, nor did Eva have a passport to leave Hungry. Moreover, communist bureaucrats made it increasingly difficult to obtain these documents. In some instances, up to six weeks might be needed. However, George and Eva were daring and resourceful. When told by a police officer that it would take at least three weeks to obtain a marriage license, George suddenly acted on impulse: “I had always heard others tell of such things but I myself had neither seen nor done it. I pulled a fairly modest bill out of my pocket and put it in the policeman’s hand. ‘Pardon me, how much time was it you said?’ ‘I’ll go get it at once,’ he answered (3).”

With similar persistence and ingenuity, George and Eva obtained all their necessary documents, and they were married that very day! One document, a certificate asserting that neither George nor Eva had a venereal disease, would normally require a three-week lab test. But they beseeched an older colleague, now a doctor at a children’s hospital, to write the certificate for them. Their colleague did so, on his Children’s Hospital stationary. George and Eva then went to the prefecture to be married, only to find a disagreeable marriage official, who was determined to leave work for the day. But, when the official leafed through their papers, and saw the venereal disease certificate written on Children’s Hospital stationary: “He laughed until tears ran down his cheeks. This was the funniest thing he had seen during his whole time in service.” He then gladly married the couple.

As the Iron Curtain descended about Hungary, George and Eva left for Sweden, where they would now continue their medical studies. What’s more, Eva joined George in Caspersson’s laboratory at the Karolinska Institute. The couple would work together at the Karolinska until George’s death at the age of 91. [Eva was born to Jewish parents in Budapest in 1925. In 1944 and 1945, she and several members of her family hid from the Nazis at the Histology Institute of the University of Budapest. Encouraged by Caspersson, Eva had an independent research career, while also collaborating with George. She is best known for discovering natural killer cells, and for generating the Burkitt’s lymphoma cell lines, which she and George studied together (see below).]

George and Eva, at the Karolinska Institute, 1979

We conclude with a brief review of some of George Klein’s contributions to virology and to cancer research.

Tumor immunology: In 1960, George and Eva used methylcholanthrene to induce tumors in mice. Next, they surgically removed the tumors, killed them with irradiation, and inoculated them back into genetically compatible mice. Next, they challenged these mice with cells from a variety of different tumors, and showed that the immune systems of the inoculated mice rejected only those cancer cells that came from the original tumor. Thus, there are tumor-specific antigens that can be recognized by the immune system. See Aside 1.

[Aside 1: Importantly, the tumor resistance seen in these experiments did not arise spontaneously in the original tumor-bearing animals. Instead, it developed in the test mice, in response to sensitization with killed tumor cells. Thus, these experiments per se do not point towards an immune mechanism of tumor surveillance. Nonetheless, harnessing such a mechanism is currently a promising means of cancer therapy, and was a major theme in Klein’s thinking.]

The following year, Klein’s group showed that polyoma virus-induced tumors share a common antigen. Importantly, polyoma virus-induced tumors, and polyoma virus-transformed cells, were rejected irrespective of whether they released virus. Thus, antiviral immunity as such was neither necessary nor sufficient for tumor rejection. This was the first demonstration that tumors caused by a virus might share a common antigen. The Kleins, and others, later found similar “group-specific” transplantation antigens on other virus-induced tumors, including retrovirus-induced lymphomas.

Burkitt’s lymphoma: “Sometime in the mid-1960s, Eva suggested that we should use our experi­ence on virus-induced murine lymphomas to examine a human lymphoma with a presumptive viral etiology. Could we detect group specific antibody responses that might be helpful in tracing a virus? Burkitt’s lymphoma (BL) was the obvious choice (3).” [Burkitt’s lymphoma, originally described by Dennis Burkitt in 1958, is a malignant B-cell lymphoma that is most prevalent in tropical Africa and New Guinea. It is the most common childhood cancer in equatorial Africa. Burkitt first proposed that the lymphoma might have a viral etiology, since its geographic distribution is like that of yellow fever, which is caused by a flavivirus. In 1964, Tony Epstein and Yvonne Barr, by means of electron microscopy, discovered a virus in cells which they cultured from BL tissue, thereby giving credence to Burkitt’s premise.]

Klein’s group identified a membrane antigen (MA) that was expressed in some BL-derived cell cultures. Werner and Gertrude Henle had previously discovered that the MA antigen is a structural protein from a newly discovered herpesvirus—the virus that Epstein and Barr first saw in 1964. Klein decided to call that virus the Epstein Barr virus (EBV). The MA antigen is now known to be one of the EBV envelope glycoproteins. Klein and collaborators later identified complement receptor type 2 (CR2), also known as the complement C3d receptor, as the cell surface attachment protein for the viral MA glycoprotein. CR2 receptors on B cells play a role in enabling the complement system to activate B cells.

By 1970, Klein’s group, in collaboration with Harald zur Hausen, found that the subset of BL-derived cell lines that express MA are, in fact, those that produce EBV. However, more than 90% of the BL cell lines, and all nasopharyngeal carcinomas, were found to contain multiple EBV genomes per cell, irrespective of whether they produced virus. Thus, only a subset of BL and nasopharyngeal carcinoma cells that harbor EBV genomes, actually produce the virus. During this time, the Henles discovered that EBV is the cause of infectious mononucleosis, and that EBV could immortalize normal B cells in culture.

Oncogene activation by chromosomal translocation: A sero-epidemiological study, begun in Uganda in 1971 by Geser and de-The, showed that children with a high EBV load are more likely to develop BL than are children with a low EBV load. Thus, the presence of EBV genomes in a B cell increases the likelihood of it turning into a BL. “But this is still not a satisfactory explanation; some essential element is obviously missing (3).”

What then is the missing event that gives rise to BL? A 1972 study by Manolov and Manolova, Bulgarian scientists working with the Kleins, found that a particular chromosomal marker, 14q+, was present in about 80% of BL tumors. After the Manolovs returned to Bulgaria, the Kleins, in collaboration with Lore Zech, used the chromosomal banding technique recently developed by Caspersson and Zech to examine the BL-cell chromosomes more precisely. They showed that the 14q+ marker was derived from chromosome 8, which broke at the same site (8q24) and underwent a reciprocal translocation with the short arm of either chromosome 2 or chromosome 22. All BLs carried one of the translocations.

Meanwhile, another research group found that carcinogen-induced mouse plasmacytomas are associated with an almost homologous chromosomal translocation. Thus, a common mechanism seemed to underlie two distinct types of tumors, in two distinct species. In each instance, a putative oncogene was translocated to an immunoglobulin locus, which might then have caused the oncogene to be constitutive expressed. A somewhat similar mechanism was reported earlier for the induction of bursal lymphomas in chickens by the avian leukosis virus (ALV) . In that instance, the cellular c-myc gene came under the control of the ALV provirus promotor. What’s more, Michael Cole’s group identified the transposed gene in BL, and in the mouse plasmacytomas, as c-myc. It is not yet clear how EBV infection promotes the chromosomal translocation.

Tumor suppressor genes: In the early 1970s, Klein, and collaborator Henry Harris, played a pioneering role in developing the concept of tumor suppressor genes. They found that when highly malignant mouse cells are fused with normal mouse cells, the hybrid cells are non-malignant when inoculated into genetically compatible mice. That is, tumorgenicity is suppressed by fusion with normal cells. However, tumorgenicity reappears after some apparently important chromosomes, contributed by the normal cell, are lost from the hybrid cells.

References:

  1. George Klein. Pieta, MIT Press, 1992.
  1. The Converging Lives of Jacques Monod, Francois Jacob, Andre Lwoff, and Albert Camus in Wartime France, Posted on the blog March 27, 2017.
  1. George Klein and Eva Klein. 1989. How One Thing Led to Another, Annual Review of Immunology, 7:1-33.