2015 award to be presented in April 2017

Richard E. Payne

The American Philosophical Society is pleased to present the 2015 Jacques Barzun Prize in Cultural History to Richard E. Payne in recognition of his book A State of Mixture: Christians, Zoroastrians, and Iranian Political Culture in Late Antiquity (University of California Press).

The title of this learned and intensely researched volume comes from the period under study. It refers to the second of 'three successive three-thousand year stages' through which Zoroastrian religion pictured world history. After a first stage of ideal creation occurred an era of struggle with evil in which humans were still caught. It was their task to work toward the coming of the third stage, which would end history and restore perfection. But the title also has another meaning, contemporary with the writer and his readers, that not only evokes a religious and political mixture where scholars have mostly seen sectarian division and violence, but points to the positive values of the mixture. This is a 'Christian success' in a steadfastly Zoroastrian world, a matter of 'East Syrian secular and ecclesiastical leaders... acquiring wealth, forming relationships with imperial authorities and establishing religious institutions that transmitted their sources of economic and political capital across generations'. There is a paradox here, and that is what the book explores in persuasive detail. How could a Zoroastrian emperor succeed in 'elevating and suppressing Christianity' at the same time? How could Christians flourish in a world that was famous for persecuting them? Professor Payne does not underplay the violence and difficulty of many moments in this history, but he shows, through a close examination of Zoroastrian theology, Christian legend and law, and the common uses of symbols of power, that there was an authentic 'synergy between Christian and Iranian institutions', and suggests that 'the legacy of the politics of mixture extended well beyond the frontiers of the Iranian world'. There is much for us to learn from this account of 'the construction of an identity' that was shared by groups 'with irresolvable religious differences'.

Richard E. Payne, a historian of the Iranian world in late antiquity, ca. 200-800 CE, is Neubauer Family Assistant Professor in the Department of Near Eastern Languages and Civilizations at the University of Chicago. He completed a doctorate in history at Princeton University. He was awarded the Bliss Prize from Dumbarton Oaks, the Crisp Fellowship from Phi Beta Kappa, a research fellowship from the German Academic Exchange Service (DAAD), and a visiting research scholarship from the Institute for the Study of the Ancient World at New York University. He was elected a research fellow of Trinity College, University of Cambridge. He joined the University of Chicago faculty in 2013.

The Barzun Prize selection committee consisted of Michael Wood (chair), Charles Barnwell Straut Professor of English and Comparative Literature, Princeton University; Glen W. Bowersock, Professor Emeritus of Ancient History, Institute for Advanced Study; and Jeffrey Hamburger, Kuno Francke Professor of German Art & Culture, Harvard University.

Todd R. Golub of the Dana Farber Cancer Institute for his work on "the individualization of cancer medicine."

The long-term goal of Todd Golub's research is the personalization of cancer treatment based on genetic principles. Currently, most cancers are diagnosed based on their microscopic appearance to an expert viewer. While this strategy is effective much of the time, the approach is imperfect, and results in mis-diagnoses in the case of molecularly distinct tumors whose appearance under the microscope is identical. Personalized medicine geared toward maximizing cures and minimizing side effects requires a move away from morphology-based cancer diagnosis and treatment planning, toward a system based on the molecular genetic features of a given patient's tumor.

Dr. Golub first approached this through the analysis of chromosomal abnormalities (translocations) present in patients with acute leukemia. He reasoned that such translocations mark the site of disruption of genes critical to leukemia development. He and his colleagues cloned a novel fusion gene that results from a t(12;21) translocation which fuses a gene discovered by Golub, named TEL, to another gene, AML 1. Dr. Golub subsequently demonstrated that the TEL/AML 1 fusion is the most common gene fusion in childhood leukemia, and furthermore, its presence is predictive of an outstanding response to chemotherapy. Eighty-one childhood acute lymphoblastic leukemia patients were studied, and all of the twenty-two TEL/AML 1 positive patients in the series were cured. This result has been confirmed by investigators throughout the world, and testing for TEL/AML 1 is now routine at all major medical centers.

The success of the TEL/AML 1 story indicated that genetic features of cancer can be extremely useful in cancer diagnosis. Unfortunately, unlike leukemias, most other types of cancer do not carry chromosomal translocations that serve to pinpoint the location of cancer-causing genes. To address this problem, Dr. Golub has recently pioneered the use of DNA microarrays (“DNA chips”) for cancer diagnosis and prediction of treatment response. He and his colleagues combined the use of microarrays with novel computational algorithms to demonstrate in seventy-two leukemia patients that, for the first time, cancer diagnosis was indeed feasible (with 100% accuracy) using the molecular genetic patterns in tumors alone. This advance moved the field one step closer to the goal of cancer diagnosis based on the intrinsic genetic properties of each patient's tumor.

Dr. Golub's most recent work has taken this one step further, namely to identify genetic patterns in tumors that predict response to therapy. In particular, he has observed that the response of fifty-eight lymphoma patients to chemotherapy is predictable based on the genetic features of each patient's biopsy. Similarly, he has shown that the response of eighty-five children with the brain tumor medulloblastoma to brain radiation is also predictable. This type of approach has great promise for guiding the selection of treatment for patients not on the behavior of the “average patient,” but rather on the predicted behavior of each individual patient. It is anticipated that this approach will result in patients being more informed about their disease, and thus better able to choose a course of action that is suitable.

James E. Crowe, Jr., of the Vanderbilt University Medical Center for his work on "neonatal immune responses to virus infection or immunization."

Dr. James Crowe has made outstanding contributions in the areas of immunity to, and prevention of, infectious diseases of children, including the understanding of immunological immaturity in infants and the development of vaccines. His work is an excellent example of taking original basic research from the bench to the patient.

His first major contribution was the demonstration that recombined monovalent fragments of antibody molecules (Fab fragments) produced in bacteria could neutralize viruses. This opened the way for further studies of the usefulness of antibodies prepared in the laboratory for use in the therapy and prevention of infectious diseases.

His studies elucidated the roles of cellular, humoral, and mucusal immunity in resistance to infection by respiratory syncytial virus (RSV), and showed that maternal antibodies in newborns suppress the development of antibodies in the infant to RSV infection.

His most important contribution from the standpoint of clinical medicine was the development of a large number of RSV strains as live attenuated vaccine candidates. These vaccines are now in large scale clinical trials on several continents. In the developing of these vaccines, he first examined the genetic basis for the attenuation of the virus.

His work has thus spanned the spectrum from basic virology and immunology to the development of a vaccine that should play a major role in the control of one of the most severe respiratory diseases of infants and young children.

Flaura K. Winston of the Children's Hospital of Philadelphia for her work on "biomechanical and psychological foundation of pediatric trauma prevention and treatment."

Dr. Flaura Winston has pioneered biomechanical epidemiology, a discipline that combines engineering, medicine, and public health in order to understand, and treat pediatric car crash injuries, the leading cause of death and acquired disability for children in the United States.

She identified the first case of air bag-associated child death. In 1998 she created, and heads, the Partners for Child Passenger Safety, which has collected information on 173,000 crashes involving more than 260,000 children. It is the leading resource for data on child passenger injuries, providing information to both vehicle manufacturers and legislative bodies. Her research and advocacy have led to drafting new federal air bag policies. Thirteen states now require booster seats for children after they graduate from child safety seats.

Having observed that children in the rear seats of small pick-up trucks are at greater risk of injury and death than those in the front seat, a reversal unique to this type of vehicle, she spurred collaborations between the National Highway Traffic Safety Administration and vehicle manufacturers to develop new test procedures and improved safety designs.

She has developed and tested a screening tool to aid emergency physicians in recognizing children and parents at risk of post traumatic stress disorder, and is currently developing interventions to prevent the development of the disorder.

Ali Gharavi of Columbia University for his work on "genetic studies of IgA nephropathy."

Dr. Ali Gharavi has demonstrated that a major gene on chromosome 6 affects the risk of IgA nephropathy, changing prevailing concepts about the pathogenesis of this disorder, and showing that disease occurrence and familial aggregation have a significant genetic basis.

The biological basis for the development of kidney failure is poorly understood, limiting the development of effective therapeutic or preventive measures. Dr. Gharavi's studies focus on IgA nephropathy, one of the most common causes of kidney failure worldwide. Familial, ethnic and geographic aggregation of IgA nephropathy has usually been considered to have environmental causes. Dr. Gharavi hypothesized that this clustering could be explained by shared genetic factors. He identified and enrolled thirty families in the United States and Italy that had two or more individuals affected, screened other family members and identified individuals with early or mild manifestations, not usually leading to referral for medical evaluation.

After performing a genome-wide search, he found that in the majority of families the disease is attributable to a single locus on chomosome 6q22-23. He repeated the findings in a new cohort of patients with IgA nephropathy. urther genealogic work and genetic analysis have led to the discovery of shared chromosomal segments among distantly related patients with no affected immediate family members. His findings provide strong evidence for a gene with large affect of IgA nephropathy.

By validating that IgA nephropathy can have a genetic cause, he has made clinicians aware that family history should be routinely investigated, and family members with urinary abnormalities should be referred for nephrologic evaluation for early therapy, before the development of renal failure. Family members with a history of urinary abnormalities are now advised against donating kidneys to affected patients. Dr. Gharavi's work on the genetic basis of IgA nephropathy changes our understanding of the pathogenesis of glomerulonephritis and renal failure.

Brendan Lee of Baylor College of Medicine for his work in "skeletal genetics and inborn errors of metabolism."

Dr. Lee has been a pioneer in the discovery of basic DNA defects in skeletal disorders. He discovered the first such defect in a form of chondrodystrophy: a defect in type II collagen in spondyloepiphyseal dysplasia. Other work has involved a form of Ehlers-Danlos syndrome and Marfan syndrome. His work in genetic metabolic disorders (the so-called urea cycle disorders) has been useful in their diagnosis and treatment.

Dr. Lee was the first to identify mutations causing achondrodysplasia and one of the first to associate the fibrillin gene with Marfan syndrome. He also was first to demonstrate mutations causing cleidocranial dysplasia and nail-patella syndrome. He developed stabilized isotope methods from measuring ureagenesis for diagnosis and management urea cycle disorders.

James A. Levine of the Mayo Clinic for his work on "energy expenditure and obesity."

Dr. Levine has elucidated the physiologic basis for the individual variation in susceptibility to weight gain in response to overeating. From observations in non-obese volunteers overfed in excess of weight-maintenance requirements, he found a 10-fold difference in fat storage. Two-thirds of the rise in total daily energy expenditure was due to increased non-exercise activity thermogenesis (NEAT), which is associated with fidgeting, maintenance of posture, and other physical activities of daily life. Changes in NEAT accounted for the 10-fold differences in fat storage and directly predicted resistance to fat gain with overfeeding. The results were interpreted as indicating that as humans overeat, activation of NEAT dissipates excess energy to preserve leanness and a failure to active NEAT may result in fat gain.

Studies quantitating differences in "posture allocation" (fidgeting and so on) indicated that obese individuals were seated, on average, two hours longer per day then lean individuals. Dr. Levine estimated that the NEAT-enhanced behaviors of the lean subjects resulted in their expending an additional 350 calories per day. Posture allocation did not change when the obese individuals lost weight or when the lean individuals gained weight, suggesting that it is biologically determined.

George Q. Daley of Harvard Medical School, Children's Hospital of Boston and the Dana Farber Cancer Institute for his work "in the area of chronic myeloid leukemia and in the application of stem cell biology to the treatment of leukemia and genetic diseases."

While still an MD/PhD student at Harvard Medical School (in the HST division) in the laboratory of David Baltimore, George Daley created a faithful model of human chronic myeloid leukemia by putting the fusion gene of the "Philadelphia chromosome" characteristic of that disorder into the mouse. This proved beyond question the causative role of the fusion gene and indirectly guided development of the remarkably effective inhibitor of the fusion gene product, Gleevec. After completion of full residency training capped off by chief residency at the Massachusetts General Hospital, Daley returned to the laboratory. His studies included investigations into the mechanism of resistance to Gleevec that occurred in some CML patients because of mutation in the active part of the fusion gene. This work prompted him to design small molecules that would overcome resistance and to undertake clinical trials.

Following on his seminal work on the pathogenesis and treatment of CML, a paradigm of stem cell disorders, Daley has devoted his efforts in the last five years to the fashioning of blood-cell stem cells that can be corrected genetically and used for bone marrow transplantation in genetic, neoplastic and degenerative disorders. His goal is to reprogram stem cells from patients with genetic diseases and put these cells back into the patient--a combination of gene and cell therapy. This goal was aided by his discovery of two genes that promote specialization into blood cells and their engraftment in the bone marrow. Daley is an active participant in discussions of the ethical and policy issues surrounding stem cell research. Long a leader in the CML field, he has emerged as a leader also in the field of stem cell research, being recently elected president of the International Society for Stem Cell Research.

2007 Autumn General Meeting

Judson Daland Prize for Outstanding Achievement in Clinical Investigation

Victor Velculescu

The 2007 recipient of the American Philosophical Society’s Judson Daland Prize for Outstanding Achievement in Patient-oriented Clinical Investigation is Victor Velculescu. The prize citation reads, “In recognition of his achievements in the identification of diagnostic and therapeutic targets through genomic analyses of human cancer.” Dr. Velculescu’s work is focused on genomic analyses of human cancer. He has pinpointed PIK3CA as one of the most frequently mutated oncogenes in human cancer and has obtained the first draft sequence of the breast and colorectal cancer genomes. These discoveries have identified a wealth of genes important in tumorigenesis and provide new opportunities for individualized diagnostic and therapeutic approaches in human cancer.

Dr. Velculescu is an associate professor of oncology at the Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University Kimmel Cancer Center. He received his M.D. in medicine and his Ph.D. in human genetics and molecular biology from Johns Hopkins. Over the past decade he has developed several approaches to investigate genes important to neoplasia, and applied these approaches to systematic mutational analyses of cancer genomes. His genome-wide mutational analysis of breast and colorectal cancers suggested that the number of mutational events occurring during the evolution of human tumors is much larger and affects a wider variety of genes than previously imagined. Dr. Velculescu's studies have paved the way for similar genome-wide mutational analyses in other tumor types and provide a basis for personalized approaches to understanding and treating cancer.

The Daland Prize selection committee consisted of chairman Victor A. McKusick, University Professor of Medical Genetics, Johns Hopkins University; Clyde F. Barker, Donald Guthrie Professor, University of Pennsylvania; John N. Loeb, Professor Emeritus of Medicine, Columbia University; Arno G. Motulsky, Professor Emeritus of Medicine and Genome Sciences, University of Washington; Thomas E. Starzl, Professor of Surgery, University of Pittsburgh School of Medicine; and Jean D. Wilson, Charles Cameron Sprague Distinguished Chair in Biomedical Science, Professor of Internal Medicine, University of Texas Southwestern Medical Center.