Monthly Archives: March 2018

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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