While they revolutionized operating-room medicine, the identification of blood groups and the discovery of the antigen known as the Rh factor — by Rockefeller Institute scientist Karl Landsteiner and colleagues — also raised several new questions in both the laboratory and the doctor’s office. While scientists across the world applied the new knowledge to existing patients, American physician and former Rockefeller researcher Philip Levine resolved a long-intractable medical mystery in an unexpected corner: the womb. For his identification of the Rh factor as a leading cause of maternal, prenatal and neonatal morbidity and mortality, Dr. Levine received a share of the 1946 Albert Lasker Clinical Medical Research Award.
While working at Newark Beth Israel Hospital in 1937, Dr. Levine, along with his colleague Rufus Stetson, began investigating the case of a stillborn baby who had died of what was then known as hemolytic disease of the newborn. Having suffered significant blood loss during delivery, the mother was given a transfusion of the father’s blood — both were type O. The woman suffered a reaction to the transfusion, leading Dr. Levine to conclude that there must exist a previously unknown blood-group antigen, present in the man’s but not in the woman’s blood. When Dr. Landsteiner — in whose Rockefeller laboratory Dr. Levine had worked for several years — published his findings on the Rh factor three years later, Dr. Levine had his culprit antigen.
Dr. Levine’s 1941 paper was the first to suggest the Rh antigen as the causative link of what was then a common maternal, prenatal and neonatal disease responsible at the time for the deaths of 10,000 babies each year in the United States. Dr. Levine hypothesized that if the Rh factor is inherited along similar Mendelian lines as the main ABO blood types, then in some cases, a child will inherit the Rh antigen from its father and be Rh incompatible with its mother. His continued studies showed that in any pregnancy, miniscule amounts of fetal blood can pass the placental barrier and enter the mother’s circulation. If the mother and child are Rh incompatible, the mother’s immune system will then produce antibodies to the child’s blood and pass them back to the child, leading to potentially fatal hemolysis and other symptoms in the fetus.
Rh disease, as it is now known, can be mild, moderate or even fatal, depending on several factors. Along with hemolysis, it can manifest in the development of unusually large organs and immature red blood cells in the fetus, and in anemia, jaundice, severe edema and dyspnea in the newborn. Dr. Levine soon determined that the incidence of Rh disease in a population was roughly proportionate to its ratio of Rh-negative to Rh-positive members. Among Caucasians, for example — the group with the largest number of Rh-negative members — about one in 10 pregnancies is Rh incompatible. He also found that though the risk of Rh disease is relatively low with a first pregnancy (about 13 percent among Rh-negative mothers), both the risk and the severity of the disease increase with each successive Rh-incompatible pregnancy, due to the accumulation of anti-Rh antibodies in the mother’s blood.
Following on the heels of Dr. Levine’s revelation, researchers set to work on a vaccine that would prevent Rh disease symptoms in non-Rh-sensitized mothers and babies and treat those that appear in patients already immune-sensitized. An antibody vaccine introduced in the 1960s and now in common use has all but wiped out the disease in developed countries. Dr. Levine shared the 1946 Lasker Award with Dr. Landsteiner as well as John Mahoney of the United States Marine Hospital and Alexander Wiener of the New York Medical Examiner’s Office.
Born in Russia in 1900, Dr. Levine came to the United States at the age of eight. He earned his medical degree from Cornell University in 1923 and joined the Rockefeller Institute laboratory of Karl Landsteiner in 1925. From 1932 to 1935, he conducted research at the University of Wisconsin, Madison, after which he joined the Newark Beth Israel Medical Center. In 1944, Dr. Levine became director of the biological division of the Ortho Research Foundation, where founded a center for research on blood groups. Ortho was later renamed the Philip Levine Laboratories. He retired in 1965. Dr. Levine served as a president of the American Society of Human Genetics, and was a member of the National Academy of Sciences and an elected fellow of the Royal College of Physicians in London. In 1969 the American Society for Clinical Pathologists established an award for clinical research in Dr. Levine’s name. Dr. Levine died in 1987.