Motulsky History

From boy…
Click here to read about Arno’s riveting war time experience as a young adult.
This article was taken from the UW Medicine magazine for alumni of the University of Washington School of Medicine, Fall 2002, Volume 25, No. 2.

To Professor…
This exerpt was taken from an article by Clement A. Finch, M.D., titled

Arno Motulsky came to the UW in 1953 as an instructor in hematology, having trained with Karl Singer in Chicago at Michael Reese Hospital and with William Crosby at Walter Reed Army Graduate School. Because of Motulsky’s interest in hereditary hemolytic anemias and genetic disorders in general, the suggestion by Department of Medicine chair Robert Williams that he spend more time in genetics fell on responsive ears. After a year at the Galton Laboratory of University College in London under Lionel Penrose, Motulsky returned in 1957 to build a division of medical genetics. This preceded the establishment of the Department of Genetics in UW’s College of Arts and Sciences by three years. Several division members later obtained joint appointments with this department.

In 1967 the division obtained a program-project grant on gene action, and in 1972 NIH funded a broadly based center. Subsequent research in human and medical genetics has been far-ranging, consistent with the many interests of Motulsky and other faculty members. UW researchers carried out population studies in many parts of the world on malaria-dependent red cell traits, with emphasis on G6PD (glucose 6-phosphate dehydrogenase). Stanley Gartler used the G6PD enzyme system to study tumor origin, which led to the demonstration by Philip Fialkow that several hematological malignancies are clonal in origin.

Motulsky performed the first successful bone marrow transplantation in an experimental animal model to eradicate an inherited red cell disease (hereditary spherocytosis in deer mice). A post-doctoral fellow, Joe Goldstein, pioneered studies on the role of genetic hyperlipidemia in coronary artery disease. Later, as a faculty member of the University of Texas at Dallas/Southwestern, Goldstein won a Nobel prize for the discovery of a cell receptor for low density lipoprotein and its influence on cholesterol metabolism. Recent studies on fetal hemoglobin production by George Stamatoyannopoulos uncovered the mechanism for the developmental switch to adult hemoglobin that may lead to a treatment for sickle cell anemia. Such research has attracted investigators from this country and abroad and has helped popularize genetics as an important basic and applied science.

Current Research

The principal theme of the work of Dr. Motulsky is the role of heredity-environment interactions in the pathogenesis of disease. Dr. Motulsky introduced the concept of genetically determined drug reactions (pharmacogenetics) and worked extensively on several pharmacogenetic traits. Current emphasis deals with the extension of pharmacogenetics to other environmental agents (ecogenetics) in conjunction with the UW center on ecogenetics. Previous studies on the frequency and genetics of hyperlipidemia in populations of patients with coronary heart disease led to the definition of the role of various genetic hyperlipidemias in coronary heart disease. Dr. Motulsky’s current work in this field focuses on the study of lipid-related genes and is being carried out at genetic and population genetic levels. Other work deals with the genetics of homocysteine elevations as a risk factor in arteriosclerotic vascular disease and polymorphisms for MT hydrofolate reductase and the role of folic acid in regulating homocysteine levels. Another aspect of Dr. Motulsky’s work is on the molecular genetics of color vision genes. Much heterogeneity was found in the molecular make-up of color vision pigment genes in individuals with normal and with defective color vision. The psychophysical perception of color is correlated with molecular gene arrangement.

By Claudia Dreifus, The New York Times – Among scientists, 84-year-old Arno Motulsky is known as the “father of pharmacogenomics.” In 1957, Dr. Motulsky, a medical doctor and researcher at the University of Washington, published an article reporting that two drugs had negative interactions with enzymes produced by certain human genes. Might this be true of other pharmaceuticals, Dr. Motulsky wondered? His question set off a revolution in research. Dr. Motulsky, who grew up Jewish in Nazi Germany, barely made his way out of wartime Europe and to safety in America.

Q. IN 1939 YOU BOARDED AN OCEAN LINER FROM HAMBURG TO CUBA WITH YOUR MOTHER, BROTHER AND SISTER. DID YOU EVER GET THERE?

A. We got as far as Havana harbor. Our ship was the S. S. St. Louis. The Cuban government had canceled the transit permits of most of the passengers — nearly a thousand refugees. We could not disembark.

Q. YOU MUST HAVE BEEN TERRIFIED.

A. I was 15. At that age, one tends to be optimistic. Many of the older men, they’d been in concentration camps and they had a better sense of what could happen. For days, appeals went out to the U.S. government to take us in. Then the Cubans ordered the St. Louis out of Havana harbor. The captain — who was a decent sort — sailed the ship up the Florida coast, hoping something would change. You could see Miami. Eventually, the St. Louis turned around for Europe. Our family was given asylum by Belgium. After a year in Brussels, we got our visas for America, but before we could leave, the country was overrun by the German Army.

Q. WERE YOU THEN INTERNED?

A. Yes, I was sent to a succession of camps in France. Though conditions were bad — hunger, typhoid — I always tried to know what was going on. I always tried to get a hold of newspapers, which was very difficult.

After many months, the Vichy French moved those internees with the possibility to emigrate to a special camp near Marseilles. We were allowed to visit consulates in the city. I spent much time at the American consulate, pleading for a renewal of my now-expired visa.

That came through right before my 18th birthday. So 10 days before I turned 18, I crossed into Spain. From there I went to Lisbon and eventually Chicago, where my father was. If my visa had taken any longer, I wouldn’t be here today because Franco had barred males over 18 from transiting through Spain; I would have ended up in Auschwitz, like most of the people I left behind.

Q. WHAT BECAME OF YOUR MOTHER AND SIBLINGS?

A. For two years, there was no news. In Brussels, they’d gotten orders to be “resettled in the East.” With the help of Belgian friends, they illegally crossed into Switzerland. We didn’t see them until 1946.

Q. HOW DID YOU BECOME A DOCTOR? THAT COULDN’T HAVE BEEN EASY FOR A PENNILESS REFUGEE KID.

A. I had a great piece of luck. When I was 20, I was drafted! The Army needed doctors for the war. They put me into a special program, where they sent me to Yale and later to medical school.

Q. HOW DID GENETICS BECOME YOUR SPECIALTY?

A. While at Michael Reese Hospital in Chicago, I met the hematologist Dr. Karl Singer, and he had all these modern ways of studying blood. That interested me. Because there are hereditary blood diseases, I soon became interested the genetic aspect of hematology.

Q. YOUR OBSERVATION IN 1957 ABOUT THE INTERACTIONS BETWEEN THE ENZYMES PRODUCED BY GENES AND SOME DRUGS — DOES IT PLEASE YOU TO SEE HOW IMPORTANT IT HAS BECOME?

A. Yes, because at first the idea was not well accepted. I remember going to an important pharmaceutical executive and I said, “I found a new way to find out about drug reactions.” And he kissed me off: “Drug reactions?”

Things also moved slowly for a long time because it was hard to test for this. But now, with the new DNA testing, you can do many things faster and better. And with the modern computerized genomics, you can even test for reactions to many different enzymes, all at the same time.

On the other hand, I think the promise of pharmacogenetics is sometimes overhyped. There are people who think we’ll be able to solve almost everything with an individualized prescription. We need more research, which will be expensive.

Q. WILL HEALTH INSURANCE PAY FOR DNA TESTING AND CUSTOM PHARMACEUTICALS?

A. That’s a problem. On the hopeful side, people say it may soon be possible to sequence a person’s genome for $1,000. Once they figure out low-cost ways to sequence the genome, the price of personalized medicine will come down.

Still, one shouldn’t be misled. What we know about the genome today is not enough for all the miracles many expect from this field. There’s a lot about what regulates the genes and how they interact that we still need to understand. We won’t have the answers by tomorrow.

Q. AT 84, YOU’RE STILL WORKING. WHAT ARE YOU TACKLING IN YOUR LABORATORY?

A. One project I’m very excited about relates to human color vision. About 8 percent of males have inherited red-green color blindness. This is caused by hereditary abnormalities in color sensitive pigments of the retinal cones in the back of the eyes, which are actually part of the brain. Our laboratory found that one-half of males with normal color vision had the amino acid alanine in their red pigment, while the other half all carried the amino acid serine, at the same site. This finding means that the same exact red color is perceived as a different type of red, depending on a person’s genetic makeup.

Q. WHAT’S THE POINT OF KNOWING THIS?

A. It’s exciting to learn that because of heredity, different people can see the same thing differently. I think this may prove useful in studying more complex brain functions. If this were 20 years ago, I’d focus on neurogenetics. What’s going on in the brain, that’s the last frontier.

Q. DO THE EXPERIENCES OF YOUR CHILDHOOD HAVE AN IMPACT ON YOUR LIFE AND WORK TODAY?

A. I often think about it. Whenever something good happens, I say to myself, “Look, you almost didn’t live to experience this.” When I see pictures from Africa, I think: “That could be me. I was once a refugee.”