The effect of cholesterol on heart attacks, different color perception in humans and genetic counseling - these are just some of the areas in which Prof. Arno Motolski, one of the most important modern geneticists, was involved. This week, in Israel, he also told about his childhood, where his attraction to genetics lies
Motulsky studied a rare blood disease in mice. "By transplanting blood cells from healthy mice into sick mice, we were able to cure the disease. This was the first time they succeeded in curing a hereditary disease with a bone marrow transplant. This is how people are treated today"
Prof. Arno Motolski wanted to immigrate to Israel when he was 14 years old, when bad winds began to blow in Nazi Germany. He was then in a youth movement, but was disqualified for aliyah due to a heart defect.
His childhood memories accompany him to this day. On Monday he arrived in Israel as a guest of honor at the conference of the Society for Genetics in Israel. The conference was held at Tel Aviv University and was entitled "Frontiers in Genetics". Researchers from Israel presented the latest developments in a variety of fields in molecular biology and medical genetics, including breast cancer in the Ashkenazi Jewish population, predicting the tendency to develop lung cancer in smokers and innovations in the genetic structure of plants.
Motulski's contribution to the study of human genetics spans over half a century. Many fronts in modern genetics were born from ideas he conceived and pioneering work he carried out during his scientific career. Today, as a first-rate American scientist, a member of the National Academy of Sciences of the United States of America and the American Association of Arts and Sciences, with more than 400 scientific articles, ten books, awards and scientific honors behind him, he tries to think about what from the distant past of his childhood influenced the direction of his work.
How Motolski became an American citizen is a dramatic story in itself. With the rise of anti-Semitism in Germany, his parents decided to immigrate to the USA. His father went to Cuba first. His mother took the three children, and together with thousands of refugees they boarded the ship St. Louis in 1939, which was the last refugee ship allowed to leave Germany. The Cuban government did not allow the ship to dock in Havana, and Miami also refused to accept the refugees. With no choice, the ship turned back to Germany. Fortunately, before arriving in Germany, four European countries (England, France, the Netherlands and Belgium) announced that they would allow about a quarter of the refugees to disembark. This is how the Motulski family found themselves in Belgium. Most of the refugees who remained on the ship ended their lives in one of the extermination camps. In Belgium, the family received a visa to the USA, but a week after receiving it, the Germans invaded Belgium. Motolski was sent to France with a group of children. His mother, brother and sister secretly crossed the border into Switzerland. At the end of the war, they all came to the USA, where the family was reunited with the father.
Motulsky graduated from medical school in the USA. He participated as an officer in the Korean War and from 1953, with the end of the army, entered the field of genetics, which began to develop. "The idea that a defect in one gene can change a protein and the result is damage to biochemical processes in the body - fascinated me," Motulsky said this week. "I was enthusiastic about the possibility of testing a defective enzyme, created by a gene mutation, and thus finding the cause of the disease. In the early 50s I started researching hereditary blood diseases. At that time, the model of the genetic code was published, but the tools to test the DNA were not yet available and they did not yet know how changes in the genetic material affect the structure of the protein."
In his studies in the genetics of blood diseases, Motolski studied a rare blood disease in humans (hereditary spherocytosis). The disease destroys red blood cells. "We had mouse models that are born with this hereditary disease, just like humans," Motulsky said. "By transplanting blood cells from healthy mice into sick mice that were born, we were able to cure the disease. This was the first time they succeeded in curing a hereditary disease through a bone marrow transplant. Today, people with various hereditary diseases are treated in this way."
In 1956 Motulsky founded the Department of Medical Genetics at the University of Washington School of Medicine in Seattle. He headed it until 1989, and continues his research there to this day. Another blood disease he researched is common in Middle Eastern countries such as Iraq and Iran for example. In Israel, the disease is common among immigrants from these countries. Due to a hereditary defect, those affected by the disease lack an enzyme called G6PD. "During the study of the disease, we noticed that in patients with G6PD deficiency, who take anti-malarial drugs, the blood cells are destroyed. In the 60s I traveled to Africa and Sardinia to study the link between enzyme deficiency and malaria. I found to my surprise that the deficiency in the enzyme protects against malaria. The malaria parasite probably needs this enzyme and therefore does not attack the patients."
The studies on G6PD deficiency indicated for the first time the relationship between genetic structure and response to drugs. Later, Motulsky observed this connection in other genetic diseases. For example, before anesthesia during surgery, patients receive a medicine to weaken the leg muscles. The drug is supposed to be broken down in the body within minutes, by a certain enzyme. For those who lack the enzyme, the drug does not break down and endangers their lives. "I came up with the opinion that the side effects of the drugs are partly due to changes in the enzymes, which cause unwanted reactions to the drugs," Motulsky says. An article he wrote on the subject, in 1957, opened a new field, pharmacogenetics, which examines the effect of genetic changes on the response to drugs.
"In order to develop the research in this field, I needed money," says Motulsky. "The pharmaceutical companies, from whom I asked for a grant, looked at me as if I had fallen from Mars. The connection between pharmacology and genetics then seemed completely absurd." This connection, between drugs and genetic structure, has been clarified since then, and surprising findings are becoming clear every morning. In the future it will be possible to develop personalized medicine, which will be designed according to the individual's genetic makeup. Motolski is considered the father of pharmacogenetics.
Studies of hereditary blood diseases led Motulski to examine the genetic background of vascular diseases. Members of his team tested whether patients who survived heart attacks had a lipid pattern in their blood, which could indicate hereditary factors for the disease. "At the time, a researcher named Yosef Goldstein worked in my team," Motulsky says. "Goldstein found that people with a very high cholesterol level may have a heart attack at a young age. This was the first step to finding the genetic background for excess cholesterol." Goldstein moved to work in Texas and in 1989 received a Nobel Prize for finding the gene, a defect in which leads to a high cholesterol level and a high risk of cardiovascular disease.
Diseases that are the result of a defect in one gene are rare. Most of the common diseases in Western society - such as Alzheimer's, Parkinson's, cardiovascular diseases, asthma, diabetes, osteoporosis, and also mental illnesses such as schizophrenia - develop due to interactions between many genes. Today's technologies make it possible to start locating some genes from the gene cluster of each disease; But there is still a long way to go until it is understood how the various genes work side by side and how the interactions between them and the environment may contribute to the development of complex diseases.
The connection between genetics and the environment gave birth to a new field - ecogenetics, and Motolsky was also among its founders. "It is relatively easy to check the relationship between genetics and the environment when it comes to the deficiency of one enzyme," he explains. "You can see this phenomenon in a hereditary disease that is common among Japanese and East Asian people, in which there is a lack of an enzyme that breaks down alcohol. These people will never get addicted to alcohol - because after drinking it they feel hot flashes."
Another example is a lack of an enzyme that breaks down lactose - the sugar found in milk. Babies have an enzyme that breaks down lactose, and this allows them to digest breast milk. With age, the enzyme disappears, and for this reason many people react to drinking milk and its products with stomachaches and various digestive problems. It turns out that people with a "milk culture" - that milk products occupy a significant place in their menu from a young age - have developed a mutation, in which the enzyme continues to be produced even after the cessation of breastfeeding.
Motulsky discovered a connection between the level of a certain enzyme in the blood, which is determined by the genetic makeup of each individual, and between the extent of the breakdown of folic acid (a group B vitamin, associated with the formation of red blood cells). "In every population there are individuals with somewhat different genetic compositions," he explains. "In those whose genetic composition leads to the creation of too little folic acid, the level of another substance, homocysteine, increases, which may increase the risk of having a heart attack. Such people should receive a supplement of folic acid in their diet. This field is called nutrigenetics - which deals with food requirements that depend on the genetic structure."
In recent years Motulsky has been interested in the molecular genetics of color vision. About 8% of men have a problem with red and green vision. They are defined as having color blindness to one degree or another. The researchers found that for the vision of each of the three basic colors - red, green and blue - a special protein, coded by a separate gene, is responsible. They also found that the gene responsible for creating the protein for red vision is not the same for everyone: in half of the population the protein is found in one version and in half - in another version. The two versions differ from each other by one amino acid.
"We tested the sensory perception of red in humans who differ from each other in the protein version," says Motulsky, "it turned out that the difference between the two versions of the gene causes a difference in the perception of the color red. In both cases you see a 'red' color, but the two reds are not the same. In other words, a small change in the garden creates a different perception of color." According to him, the same thing may also happen in the nervous system: "Perhaps each of us perceives the environment in a different way, due to variations in the nervous system between people. This may be the first clue to molecular psychology."
Israel is "every geneticist's dream", says Motulsky, who over the years has done a lot of research on Jewish populations. He studied genetic diseases among Ashkenazi Jews and the genetic aspects of Jewish history. "It is possible that the tendency to research genetics and Jewish history is rooted in my past memories in Europe," he says. In the 70s he examined the Ashkenazi Jewish population in Europe. He found that 12% of the Jewish-Ashkenazi genetic pool in Europe comes from a non-Jewish source. Motulsky was one of the founders of genetic counseling, and over the years nurtured generations of geneticists who gained international fame.
The most exciting field that he predicts will develop in the future is neurogenetics - understanding the interrelationship between genetics and neuroscience. "If I had to start my research in the field of genetics today, this is the field I would choose," he said. "We understand the human genome and genetic mechanisms fairly well, but know very little about the brain. I would like to go into hibernation today and wake up in 40 years."
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