"In physical science the first essential step in the direction of learning any subject is to find principles of numerical reckoning and practicable methods for measuring some quality connected with it. I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely in your thoughts advanced to the state of Science, whatever the matter may be."– Sir William Thompson (Lord Kelvin), 1883 (one of Louis Sokoloff's favorite quotations)
During a research career spanning nearly sixty years, physician and neuroscientist Louis Sokoloff transformed the study of brain structure and function with the quantitative methods and tools he developed to measure cerebral blood flow and metabolism. Using radioactive 2-deoxyglucose tracers, he was able to make real-time images of the brain under various physiological conditions, showing which brain regions were most active at a given moment. This work, which accurately linked regional metabolic activity to particular brain functions, constituted a quantum leap for brain-mapping research. Sokoloff's fundamental research was also "translational," as it provided the foundation for non-invasive studies of human and animal brains using positron emission tomography (PET) scanners. PET scanning technology became invaluable for both clinical diagnosis and experimental work, allowing imaging of brain disorders such as epilepsy, schizophrenia, and dementia, as well as cancers in the brain and other areas of the body.
Sokoloff was born on October 14, 1921, in Philadelphia, Pennsylvania, to Morris and Goldie Sokoloff. He was the second of their two children. His parents were both Jewish immigrants, his father from Ukraine, and his mother from a village along the Polish-Russian border. Morris Sokoloff was a tailor, and his wife a homemaker; though neither had much formal schooling, they strongly believed in the value of education for their children.
Louis embraced learning from the start; he would later recall that his earliest memory of gifts was books, and he became a voracious reader. His brother Nathan, six years older, helped to foster an early interest in biology; Nathan's terrarium prompted Louis to observe and read about the animals and plants. Later on, Nathan majored in zoology and then attended medical school at the University of Pennsylvania, and his textbooks were available to his brother. Like many budding scientists of that era, Louis was influenced by Paul DeKruif's The Microbe Hunters and other popular works. Perhaps less typically, he was also inspired by Chemistry in Medicine, a free publication of the Chemical Rubber Company, which published the standard reference work Handbook of Chemistry and Physics. A neighbor, high school math teacher Israel Abrams, also encouraged and guided his science reading. Sokoloff's interests also extended beyond math and science. His experiences of the Great Depression (and the rise of fascism) drew him to the study of politics, economics, and history, especially that of modern Europe. He worked hard and did well at school, but also developed a passion for baseball, and later on, tennis, which he would enjoy playing all his life.
Sokoloff graduated first in his class from South Philadelphia High School for Boys in 1939. This entitled him to a Philadelphia Board of Education college scholarship to the University of Pennsylvania, where he pursued a liberal arts and sciences curriculum with a major in zoology and a minor in chemistry. For practical reasons, he planned to apply to medical or veterinary school after that. In his third undergraduate year, however, he took Lewis V. Heilbrunn's two-semester general physiology course, which convinced him to pursue a research career. Heilbrunn was the author of an influential textbook on cell physiology, and one of the first investigators to argue that calcium played an important role in biological processes. A demanding teacher and researcher, he was also accessible to students and fostered intellectual discussions and camaraderie. For his senior year research elective, Sokoloff worked with Heilbrunn on a study of the heat sensitivity of muscle and nerve tissue, part of a research series done under a wartime grant. He received his BA from the University of Pennsylvania in 1943.
World War II forced Sokoloff to change his post-graduate plan to pursue doctoral work with Heilbrunn. His mentor warned him that he would have to abandon any graduate projects if he were drafted, and advised him to go to medical school instead, because medical students were being allowed to finish their degree work before starting military service. With an excellent scholastic record and Heilbrunn's strong recommendation, Sokoloff was admitted to the University of Pennsylvania School of Medicine. Because of the war, many medical school programs were compressed into three years, so he started his medical training in spring of 1943, immediately after earning his BA.
Sokoloff received his MD from the University of Pennsylvania in 1946 and did a rotating internship at Philadelphia General Hospital. Due to the phase-out of the wartime accelerated program schedule, the internship was extended by six months, so that Sokoloff got an extra half-year on a neuropsychiatry rotation. The experience enhanced his competence in psychiatry as well as his interest in the possible physiological origins of mental functions, and helped shape his later research direction.
During his last year of medical school, Sokoloff met Betty Kaiser, a U.S. Navy nurse stationed in Philadelphia. They were not supposed to "fraternize," because Betty, as a Navy ensign, outranked Sokoloff, who was still only a U.S. Army private under the Army Specialized Training Program for medical personnel. (He would be promoted to first lieutenant after graduation.) They defied the rules and dated anyway, and were married in January 1947. They had two children, a son and a daughter.
From August 1947 to August 1949, Sokoloff served as Chief of Neuropsychiatry in the U.S. Army's station hospital at Camp Lee, Virginia. His experiences there convinced him to pursue research into the physiological rather than psychodynamic origins of mental disorders. After leaving the army, he returned to Philadelphia, and began a research fellowship with Seymour Kety at the University of Pennsylvania's Department of Physiology and Pharmacology. Kety had recently developed a new method for measuring rates of cerebral blood flow and metabolism, using nitrous oxide, and Sokoloff was intrigued by the method's potential for studying the brain in psychiatric disorders. For the next four years, Sokoloff honed his research skills on projects using the nitrous oxide method to assess blood flow and oxygen use in the brain, and studied how they were affected by sleep, hyperthyroidism, and various drugs.
In 1953, at Kety's invitation, Sokoloff joined the research staff at the Laboratory of Neurochemistry at the National Institute of Mental Health (NIMH). Kety had left Philadelphia in 1951 to become Scientific Director of the new joint intramural research program of the NIMH and the National Institute for Neurological Diseases and Blindness (NINDB) at the National Institutes of Health. There, with Kety's team in the section on Cerebral Metabolism, Sokoloff began working on new methods to measure local cerebral metabolic activity. Using various radioisotope labeled tracers, they were able to produce images of the cerebral blood flow in experimental animals. He also returned to the study of the effects of thyroid hormone on cerebral metabolism. Collaborating with biochemist Seymour Kaufman, he demonstrated that in brain tissue, thyroxine stimulates amino acid incorporation into protein (protein metabolism), rather than increasing metabolic rate by stimulating energy metabolism.
By 1957 Sokoloff was Chief of the Section on Cerebral Metabolism, and in 1968 became chief of the Laboratory of Cerebral Metabolism, a post he would hold until his retirement in 2004.
From the late 1950s, Sokoloff continued to investigate the mechanisms of thyroxine and protein synthesis in the brain. He also began considering how radio-labeled 2-deoxyglucose (a chemical analog of glucose that is taken up by cells but can't be completely metabolized) might be used to track rates of glucose utilization in specific regions of the brain to show the activity. He collaborated with former NIMH colleague Martin Reivich to design a model for calculating local glucose use, but they were dissatisfied with the equations they formulated (based on Kety's blood flow and tissue-blood exchange formulas) and dropped the project for several years.
During a sabbatical at the Collége de France in 1968-69, Sokoloff worked on a project that used enzyme reactions to study how thyroid hormone is synthesized in the thyroid gland. He realized that a model based in enzyme kinetics (which measures the reaction rates of chemical reactions catalyzed by enzymes), rather than just blood flow rates, as in Kety's model, might offer a way to track cerebral glucose metabolism. Over the next decade he and his NIMH team developed an improved method using a 2-deoxyglucose (2-DG) tracer, and showed definitively that functional activity levels in specific brain regions were linked to metabolic levels in those areas. The images produced could be further analyzed to determine relative concentrations of activity (as indicated by the presence of tracer). Doing this manually was tedious and time-consuming, so the team collaborated with several computer scientists at NIMH to develop an image-processing program that could scan and reconstruct the radiographic images, and assign different colors to the different levels of metabolic activity.
Adapting this method to studies of the human brain required a different, non-invasive imaging technology and a modified tracer. To obtain the 2-DG tracer images (autoradiographs) in their animal experiments, Sokoloff and his colleagues had to euthanize the rats or monkeys soon after the tracer was introduced, preserve the brains, then prepare thin sections of tissue and expose them on x-ray film. Clearly, this couldn't be done in human studies. Fortunately, by the mid-1970s, several researchers in the U.S. and in Europe had developed the first computerized scanning technologies for clinical use. The NIMH team worked with David Kuhl, Michael Phelps, and Edward Hoffman of UCLA, who had pioneered the development of positron-emission tomography (PET) scanners. Using a modified 2-DG tracer, PET scanning made it possible for the first time to make images of the functioning human brain and map the activity, by measuring quantitative changes in blood flow and glucose metabolism. Sokoloff received the Albert Lasker Clinical Medical Research Award in 1981 for this path-breaking work.
As Sokoloff and his research group pursued further brain-mapping studies using the 2-DG method, a controversy developed regarding the validity of the method. Several other researchers argued that Sokoloff had underestimated the activity of a metabolic enzyme, glucose-6-phosphatase, in his formula, thus skewing any measurement of the metabolic reaction. Although Sokoloff and his colleagues had carefully ruled this out as they developed the method, it took nearly a decade to prove their critics wrong.
With these new tools, research in brain mapping expanded rapidly. Sokoloff's lab continued to make increasingly finer delineations of brain function, in human subjects as well as in experimental animals. They explored the actions of drugs, hormones, and neurotransmitter chemicals in different parts of the brain, as well as the effects of aging, and diseases such as Parkinson's syndrome. In 2004, Sokoloff retired, but continued to collaborate with other neuroscientists, as a NIH Scientist Emeritus for another decade.
Sokoloff authored over 450 publications; he served as editor-in-chief of the Journal of Neurochemistry (1974-1977), president of the American Society for Neurochemistry (1977-1979), president of the Association for Research in Nervous and Mental Disease (1983), and founding member and first president (1981-1983) of the International Society for Cerebral Blood Flow and Metabolism. His honors and awards include election to National Academy of Sciences in 1980; a Lasker Award in 1981; election to American Academy of Arts and Sciences in 1982, and the American Philosophical Society's Karl Lashley Award in 1987. In 1988, Sokoloff and Seymour Kety shared the first National Academy of Sciences Award in the Neurosciences. He was also awarded honorary doctorates from the University of Lund (1980), Yeshiva University (1982), University of Glasgow (1989), Phillips University of Marburg (1990), Georgetown University (1992), University of Rome (1992), Michigan State University (1993), and the University of Pennsylvania (1997).
Sokoloff was truly a "scientist's scientist." As his colleague Gerald Dienel noted, "Lou's mastery of medicine, biochemistry, physiology, neuroscience, mathematics, and kinetic modeling enabled him to tackle and solve technically difficult problems and devise novel experimental methods that were easily adapted for use by others." He had a boundless enthusiasm for all aspects of neuroscience, and his carefully planned, high-quality research projects inspired his many students and colleagues. Beyond the lab, his interests included tennis, carpentry, and home electronics projects (e.g., building stereo systems). He was also an early adopter of computer technology, likely because of its potential for helping with all the data-crunching his work demanded. He loved good food and wine, especially French cuisine, and frequently hosted his scientific colleagues for evenings of "good science, good jokes, and good food."
Dr. Sokoloff died on July 30, 2015, in Washington, DC, following a brief illness.